tbuckley/cabot-search huggingface dataset:
Graft dysfunction in chronic antibody-mediated rejection correlates with B-cell–dependent indirect antidonor alloresponses and autocrine regulation of interferon-γ production by Th1 cells
Authors: Kin Yee Shiu, Laura McLaughlin, Irene Rebollo-Mesa, Jingyue Zhao, Hannah Burton, Harriet Douthwaite, Hannah Wilkinson, Vikki Semik, Philippa C. Dodd, Paul Brookes, Robert I. Lechler, Maria P. Hernandez-Fuentes, Claudia Kemper, Anthony Dorling
Journal: Kidney International (2016)

Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell–driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.
PWE-009 Per oral cholangioscopy: systematic evaluation in clinical practice
Authors: L Dwyer, N Polavarapu, S Hood, J Sheard, R Sturgess
Journal: Gut (2010)

<h3>Introduction</h3> A new technological approach to per oral cholangioscopy (POC) has led to a re-examination of this technique for diagnosis and therapy of hepatobiliary disease. We present a single centre experience from a tertiary regional hepatobiliary unit. <h3>Methods</h3> Prospective analysis of indications and technical success including direct visualisation, tissue acquirement and analysis and therapeutic success. Analysis of contribution of POC to clinical decision making. <h3>Result</h3> Since June 08 to date 36 ERCPs have been undertaken with POC. The indications were indeterminate strictures 28/36 (78%), filling defect 4/36 (11%), POC directed electro-hydraulic lithotripsy (EHL) 4/36 (11%). In one case the bile duct could not be intubated with the cholangioscope. Good views were obtained in 34 of 36 cases (94%). Biopsies were attempted in 16 patients, all of whom had focal mucosal change. Biopsy was not attempted if the mucosa appeared completely normal. In 15 of the 16 cases biopsy was successful in obtaining useful tissue for assessment. 12/15 biopsies were judged to be accurate on basis of either a positive diagnosis of malignancy or a non-malignant result in patients who subsequently had a benign clinical course. Three of the four cases of filling defect were shown to be stones and one a carcinoma. EHL lead to complete stone clearance in three of four cases. The addition of POC appeared to critically influence clinical decision making in 21 of 32 cases (65%). There no significant complications related to the POC procedure that could be identified. <h3>Conclusion</h3> POC is currently being re-evaluated in the management of complex hepatobiliary disease. It appears to be safe and add significantly to the information used to manage patients with indeterminate strictures and filling defects. It is undoubtedly useful for the management of complex stone disease. We initially restricted our use of POC to the most challenging patients whom had previously undergone multiple ERCP9s. We intend to evaluate POC further as a primary ERCP technique in patients with proximal biliary strictures.
150. Liver Directed Gene Therapy Using Non-Viral Minicircle-DNA Vector for Ornithine Transcarbamylase Deficiency (OTCD)
Authors: Hiu Man Viecelli, Andrea Schlegel, Sereina Deplazes, Sharon Cunningham, Ian Alexander, Johannes Häberle, Beat Thöny
Journal: Molecular Therapy (2015)

As an alternative to (AAV-) viral vector-transduction, we are using minicircle (MC) naked-DNA vectors devoid of any viral or bacterial sequences for delivery into the ornithine transcarbamylase (OTC) deficient murine model, Spfash. The MC-vectors which do not have a defined size limitation contained expression cassettes with a short (0.3 kb) synthetic liver-specific promoter or the natural (endogenous) Otc promoter with a length of up to 2 kb, the murine Otc-cDNA (mOtc) or the codon-optimized murine Otc (mcoOtc) with or without truncated 5'-intron, and a polyA signal. MC vectors were delivered to mouse liver by hydrodynamic tail vein injection. Upon sacrificing mice 2-3 weeks after vector infusion, transgenic OTC enzyme activity was found in liver extracts to be up to 2 or 3-fold higher than in normal wild-type controls. However, similar to what we have observed in our study to correct hyperphenylalaninemia in the phenylketonuria (PKU) mouse using hydrodynamic injection of MC vectors (Viecelli et al., Hepatology 2014), gene expression was mainly found at the perivenous area also in the OTC-treated mouse liver. Since the full active urea cycle is restricted to the periportal area and thus delivery of MC vectors to treat OTC deficiency needs to target these periportal hepatocytes, we have established delivery via hydrodynamic portal vein injection for gene transfer into Spfash mice. Preliminary analysis showed transgene expression in MC-treated mice however at a much lower level than via hydrodynamic tail vein injection. Analysis of urinary orotic acid and in vivo ureagenesis is ongoing for the evaluation of the therapeutic efficacy.
Myeloablative Conditioning with Intravenous Busulfan In One Daily Dose and Fludarabine (BUF) for HLA-Identical Sibling Allogeneic HSCT In Myeloid Malignancies
Authors: Javier De la Serna, Jaime Sanz, Arancha Bermudez, Carlos Vallejo, David Serrano, Dolores Caballero, Rafael De La Camara, José M. Moraleda, Sonia Gonzalez, Ana García-Noblejas, M. Cabrero, Juan José Lahuerta, Arturo Iriondo, Luis Benlloch, Guillermo Sanz
Journal: Blood (2011)
Prognostic Significance of Interim 18f-FDG PET/CT for the Treatment of Diffuse Large B-Cell Lymphoma In the Post-Rituximab Era.
Authors: Deok-Hwan Yang, Jung-Joon Min, Ho-Chun Song, Yong Yeon Jeong, Woong-Ki Chung, Soo-Young Bae, Jae-Sook Ahn, Yeo-Kyeoung Kim, Hee-Seung Bom, Ik-Joo Chung, Hyeoung Joon Kim, Je-Jung Lee
Journal: Blood (2010)
Abstract 4350: Prognostic potential of epithelial to mesenchymal transition in prostate cancer at first presentation
Authors: Ahmad Al-Sukaini, Claire Hart, Richard Robinson, Mick Brown, Noel Clarke
Journal: Cancer Research (2015)

Abstract Introduction and Objective: Metastatic progression of prostate cancer requires a change of state, epithelial to mesenchymal transition (EMT), reducing cell to cell adherence and contact, with associated cell motility and invasion. EMT is one of the hallmarks of cancer and characterisation of the EMT process has defined a panel of EMT biomarkers. Here we investigate the potential of an EMT panel of biomarkers in an unscreened population at first presentation with prostate cancer. Methods: A prostate Tissue Micro Array (TMA) comprising 2,450 cores containing normal adjacent, prostatic intraepithelial neoplasia and malignant prostate tissue from 524 diagnostic biopsies, linked to an extensive clinical database with long-term outcome, was studied. Expression of a panel of EMT biomarkers, including E-cadherin and vimentin, was assessed using an automated, high throughput fluorescent staining (Leica BOND-MAX), image capture (Carl Zeiss Microimaging Mirax scanner) and quantitative image analysis (Definiens Tissue Studio) protocol. Definiens H-Score was converted to pathological scores prior to univariate and multivariate Cox proportional hazards regression analysis in SPSS. Results: Expression of an EMT profile predicted a significant reduction in both overall and cancer specific survival. In univariate analysis, low or negative E-cadherin staining was associated with a reduction in median overall survival by 45 months (95% CI: 10.4-79.6; P&amp;lt;0.0001) and a cancer specific mean survival of 80.1 months (95% CI: 45.7-114.5; P&amp;lt;0.0001) when compared to high and intermediate E-cadherin staining. Similarly, high EMT expression, defined as loss of E-cadherin and presence of vimentin, was compared to low EMT expression, defined as preserved E-cadherin and the absence of vimentin. There was a greater reduction in overall median survival in high EMT tumours of 54 months (95% CI: 12.5-95.5; p&amp;lt;0.0001) and cancer specific survival of 93.2 months (95% CI: 62.8-123.7; p&amp;lt;0.0001) when compared to low EMT tumours. Stage, grade, PSA at diagnosis and EMT status was included in the multivariate analysis for cancer specific survival. Both Gleason grade (p = 0.017) and EMT status (p = 0.030) were found to be significant prognostic factors in predicting cancer specific survival. Conclusions: Loss of E-cadherin and concomitant expression of the EMT marker vimentin are powerful predictors of prostate cancer outcome at first presentation. Citation Format: Ahmad Al-Sukaini, Claire Hart, Richard Robinson, Mick Brown, Noel Clarke. Prognostic potential of epithelial to mesenchymal transition in prostate cancer at first presentation. [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 4350. doi:10.1158/1538-7445.AM2015-4350
A Canadian Expanded Access Trial of Oral Nilotinb in Adult Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase
Authors: Robert Delage, A. Robert Turner, Brian Leber, Wanda S. Hasegawa, Denis-Claude Roy, Mary Lynn Savoie, Heather A Leitch, Isabelle Bence-Bruckler, Donna L. Forrest, Sindu Kanjeekal, Sehdev Sandeep, Pierre Laneuville, Sarit Assouline, Kuljit Grewal, Michael J. Kovacs, Wendy Lam, Annie Woo, Pierre Beauparlant, Jeffrey H. Lipton
Journal: Blood (2011)
Gradually Progressive Spastic Ataxia in a Young Man
Authors: Divyanshu Dubey, Pravin Khemani, Eric Remster, Jeffrey L. Elliott
Journal: JAMA Neurology (2016)

A 26-year-old right-handed man presented with progressive gait imbalance over 6 years. His examination was consistent with cerebellar and upper motor neuronal dysfunction. He had no significant family history. Most of the serum and cerebrospinal fluid studies were unremarkable. Neuroimaging was remarkable for mild cerebellar and noticeable thoracic spinal cord atrophy. The initial differential diagnosis for the patient's presentation was broad, but because of certain clinical characteristics, it was later focused on hereditary ataxias. Detailed analysis of the clinical features in the history, neurologic examination, and neuroimaging studies led to the diagnosis.
112. A Novel Oncolytic Adenovirus Based on Human Adenovirus Serotype 17
Authors: Johannes Dörner, Wenli Zhang, Jing Liu, Manish Solanki, Philip Boehme, Anja Ehrhardt
Journal: Molecular Therapy (2015)

Most existing oncolytic adenoviruses (AdV) are based on human AdV type 5 from species C (hAdV-C5). Clinical efficacy of hAdV-C5 based oncolytic viruses is limited by variable expression levels of coxsackie- and adenovirus receptor (CAR) in different tumour cells and insufficient replication rates. Additionally, patients exposed to AdV develop serotype specific neutralizing antibodies compromising reapplication. Thus, development of novel oncolytic AdV based on other serotypes may help overcoming these limitations. It may additionally allow repeated dosing in humans and add to the repertoire of antitumour agents in general. We further hypothesised that oncolytic efficacy of the candidate virus can be augmented by expression of RNAi suppressor protein P19 (Lecellier et al., Nature 2005) as has been shown previously for hAdV-C5 (Rauschhuber et al, Sci. Rep. 2013). Based on a computational model AdV of species D including type 17 (hAdV-D17) are predicted to have the highest probability of expressing pre-miRNA compared to other group AdV (Pfeffer et al, Nat. Methods 2005). Moreover, high infection efficiency of EA.hy926 cells, a vascular endothelium tumor cell line that lacks CAR (Jing Liu, unpublished) with AdV17 as well as absence of cross-reactivity with AdVC5 may allow exploitation for AdV-C5-insensitive tumors and systemic therapy. Here we aim at evaluating a novel hAdV-D17-based, p19-containing oncolytic AdV as novel candidate for oncolytic applications in different major tumour cell lines and for toxicity in non-malignant cells. Thus, we cloned hAdV-17 and a P19-containing hAdV-D17 based virus by a novel seamless recombineering technique (Zhang et al, unpublished). In order to allow P19 expression from the adenoviral vector genome, the P19 cDNA was fused via an internal ribosome entry site (IRES) to the late fiber gene. To obtain control viruses, GFP was fused via an IRES to the late fiber gene. After release of the respective recombinant adenoviral genomes from plasmids containing the complete DNA molecule, linearized viral DNA was transfected into A549 cells to perform rescue experiments. To evaluate oncolytic potential we are currently comparing it with wild-type hAdV-D17 and hAdV-C5 using common oncolytic essays. Evaluation in primary tumour cells and eventually in an animal model will allow making assumptions about feasibility of oncolytic virotherapy with this vector. In total we believe that HAdV17-based vectors hold promise for oncolytic applications and may be improved by RNAi-suppression.
Direct and Enhanced Cytotoxicity of the Bcl-2 Family Inhibitor GX15-070 on Rituximab-Sensitive and Rituximab-Resistant B-NHL Clones.
Authors: Melisa A. Martinez-Paniagua, Mario I. Vega, Sara Huerta-Yepez, Bernardo Martinez-Miguel, Rogelio Hernandez-Pando, Cesar R. Gonzalez-Bonilla, Benjamin Bonavida
Journal: Blood (2007)
High response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin lymphoma, including those meeting GELF criteria.
Authors: F. Samaniego, F. Hagemeister, P. Mclaughlin, L. W. Kwak, J. Romaguera, M. A. Fanale, S. S. Neelapu, L. Fayad, R. Z. Orlowski, M. Wang, L. Lacerte, N. H. Fowler
Journal: Journal of Clinical Oncology (2011)

8030 Background: Lenalidomide has been shown to have single-agent activity in relapsed NHL, and rituximab (R) is effective alone and in combination with chemotherapy in untreated patients. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, advanced stage, indolent NHL. Methods: Pts with measurable (>1.5 cm) untreated indolent NHL received 20 mg/day of lenalidomide on days 1-21 and rituximab 375 mg/m2 on day 1 of each 28 day cycle. Prophylactic growth factors were not used. Response was assessed every 3 cycles using the 1999 International Working Group Response Criteria. Results: 75 pts have completed 6 cycles of treatment or are off-study, and 70 pts are evaluable for response. Histologies included: CLL/SLL n=15, FL n=41, and marginal zone lymphoma n=19. The median age was 57 (35-84) years, and 55% were male. The overall response (OR) rate for all pts was 90% with 66% attaining a complete response (CR). Seventeen pts (25%) had a partial response, and stable disease was noted in 6 (9%). OR and CR rates were impressive in FL, with nearly all evaluable patients 34/39 (87%) attaining a CR. At study entry, 80% of FL pts had a FLIPI score of ≥ 2, and 54% met GELF criteria for high tumor burden. Responses were high regardless of FLIPI score or GELF (CR/CRu 90% with and 83% without GELF) criteria. Following cycle 6, nearly all FL patients demonstrated molecular response with the absence of detectable BCL-2 by PCR. At a median follow up of 14.4 (7-32.5) months, 4 patients experienced progression of disease. The most common grade ≥ 3 non-hematologic toxicities included rash (7 pts), muscle pain (7pts), thrombosis (3pts) and infection (3pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 20 (27%) and 4 (5%) pts respectively. Five pts stopped treatment due to adverse events, all of which occurred during the first two cycles. Conclusions: The biologic agents lenalidomide and rituximab used as front line therapy produce excellent overall and complete response rates with manageable toxicity in pts with indolent B cell NHL. Randomized studies are planned utilizing this regimen in untreated follicular lymphoma.
OC-057 Safety and comfort for colonoscopy in the over seventies—time to achieve a balance?: Abstract OC-057
Authors: F Ali, J Hancock, A Sarkar, J Parr
Journal: Gut (2010)

<h3>Introduction</h3> The BSG has published guidelines suggesting maximum sedation doses for patients aged over 70 years.1 Elderly patients have greater co morbidity and potential for complications from sedation at lower doses than younger patients.2 We investigated whether the maximum doses as suggested by the BSG resulted in adequate pain relief and patient perception that adequate sedation was given. <h3>Methods</h3> A prospective study of patients aged over 70 years of age attending our unit to undergo colonoscopy. Data were collected on patient reported pain scores (visual analogue score 0–10) during colonoscopy, sedation and doses used. Patients completed a post endoscopic questionnaire to ascertain if more or less sedation would be preferred for future endoscopic procedures. ASA grade was also assessed. All colonoscopists in the study had caecal intubation rates of at least 85%. <h3>Results</h3> 183 patients were included (96 Male and 87 Female). 74 patients received the maximum recommended sedation dose. Of those, nine would prefer less sedation, 44 the same, 11 more. Eight would refuse a further procedure and five were undecided. With those who requested more sedation, three patients had an ASA grade of 3 or more. Patients requesting more sedation had higher reported pain scores than those who were satisfied with the sedation they received (mean pain score 4.68 vs 1.51). 20 patients received less than maximal sedation, eight would choose the same sedation again, six more and three would refuse a future test. The average ASA score in those requesting more sedation was 1.98. 89 patients received more than the recommended dose of sedation, (mean Midazolam (M) 3.11 mg (range 2.5–5 mg). Mean Fentanyl (F) 94.7 μg (range 75–100 μg)). Average ASA score was 1.69. In this group 56 wanted the same sedation, 1 less, 17 more and 4 patients would refuse a future test and 11 were unsure. 14 of the 89 had more than recommended doses of both M and F. No adverse events were reported for any patients. <h3>Conclusion</h3> Sedation doses recommended by current BSG guidelines appear inadequate for a significant proportion of elderly patients under going colonoscopy. Failing to address patient comfort for safety would appear to have a negative affect on the acceptability of the procedure.
Abstract 4217: Targeting head and neck cancer-initiating cells with combinatorial therapeutics through pharmacological inhibition of ROS scavenger and conventional chemotherapy
Authors: Ching-Wen Chang, Jeng-Fan Lo
Journal: Cancer Research (2015)

Abstract Background: Cancer-initiating cells (CICs) contribute to tumor initiation, progression and therapy resistance through critical physiology mechanisms. Redox homeostasis plays an important role in the regulation of cancer stemness. We recently have reported that cancer cells containing differential level of ROS display distinct physiological properties of stemness, proliferative activity, chemoresistance and tumorigenicity. Therefore, to uncover the regulatory physiological mechanisms by which to sustain the low lever of ROS in CICs warrants an important study for future therapy development. Results: In this study, we demonstrated that lower ROS levels in head and neck CICs (HN-CIC) enriched population are associated with increased expression of ROS scavenger such as catalase and SOD2. Pharmacological and genetic inhibition of SOD2 or catalase caused the increased expression of differentiation marker, cytokeratin 18, but the decreased expression of CIC marker in HN-CICs. In addition, the sphere formation abilities of HN-CICs under genetic inhibition of SOD2 or catalase were also significantly abolished. Notably, combinatorial treatment with ROS scavenger inhibitors and conventional anticancer drugs synergistically reduced the stemness properties and tumorigenicity both in vitro and in vivo. Using the Oncomine database, we found associations between SOD2 and catalase expression and increasing head and neck cancer recurrence, tumor invasion and resistance to Gemcitabine treatment. Conclusion: Together, these data demonstrate the importance of antioxidant defense to maintain the low ROS level, cell viability and chemosensitivity of HN-CICs. Pharmacological inhibition of ROS scavenger (SOD2 and catalase) might be a future alternative HNSCC treatment in combination with conventional chemotherapy Citation Format: Ching-Wen Chang, Jeng-Fan Lo. Targeting head and neck cancer-initiating cells with combinatorial therapeutics through pharmacological inhibition of ROS scavenger and conventional chemotherapy. [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 4217. doi:10.1158/1538-7445.AM2015-4217
Effects of an ErbB-3 antibody, MP-RM-1, on tumor growth and ligand-dependent and -independent activation of ErbB-3/akt signaling.
Authors: S. Iacobelli, G. Sala, S. Traini, M. D'Egidio, G. Vianale, C. Rossi, E. Piccolo, R. Lattanzio, M. Piantelli, N. Tinari, S. Gildetti, D. D'Addario, J. Giampietro, P. G. Natali, R. Muraro
Journal: Journal of Clinical Oncology (2011)

e13538 Background: The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand binding molecule that abrogates ErbB-3 mediated signaling. Methods: we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. The ability of the antibody to suppress NRG-1b-dependent and independent ErbB-3 signaling was evaluated in vitro by western blotting using a panel of human tumor cell lines (breast, melanoma, stomach and prostate) as well as early passage tumor cells obtained from patients. The effect on tumor growth in vitro was evaluated with clonogenic assay and in vivo using human tumor xenograft nude mouse models. Results: MP-RM-1 effectively inhibited NRG-1b stimulated and basal ErbB-3/Akt activation. Treatment with the antibody led, in most instances, to a decreased ErbB-3 expression. In addition, MP-RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in human melanoma and prostate carcinoma xenografts. Tumors from animals treated with the antibody displayed a lower ErbB-3/Akt phosphorylation that was accompanied by a decreased ErbB-3 expression. Conclusions: MP-RM-1 has the potential to interfere with signaling by ErbB-3/Akt signaling and can be regarded as a potential candidate for clinical development.