tbuckley/cabot-search huggingface dataset:
Abstract 12006: Renal Sympathetic Denervation Improves Both Progressive Cardiac Remodeling and Renal Damages in Hypertensive Heart Failure Rats: Comparison With β Receptor Blockade
Authors: Heitaro Watanabe, Yoshitaka Iwanaga, Yuki Miyaji, Hiromi Yamamoto, Shunichi Miyazaki
Journal: Circulation (2015)

Background: Chronic activation of sympathetic-nervous system (SNS) is triggered and contributes to subsequent cardiac remodeling and the transition to heart failure (HF). Hypothesis: Renal sympathetic denervation (RDN) may affect the process by improving the renal damage and suppressing cardiac SNS in rat hypertensive HF model with renal injury. The effects may be comparable to those of chronic β blocker treatment. Methods and Results: In Dahl salt-sensitive hypertensive rats, RDN or sham operation was performed at hypertrophic stage (11 weeks). Vehicle (CONT) or β blocker, bisoprolol (BISO) was administrated in rats with sham operation. Both RDN and BISO did not alter blood pressure during the study, but BISO group showed the significantly less heart rate. In RDN and BISO groups, the median survival time was significantly improved from 18.9 (CONT) to 21.4 and 22.5 weeks, respectively (P &lt; 0.01). Echocardiography showed the improvement of LV dilatation and fractional shortening, and histological analysis showed the amelioration of myocyte hypertrophy and fibrosis in RDN and BISO groups at HF stage (17 weeks). β1 adrenergic receptor and tyrosine hydroxylase expression in LV myocardium was significantly increased only in RDN group. In contrast, α1b, α1d, and α2c adrenergic receptor expressions were improved only in BISO group. Furthermore, renal histopathologic damages and function were ameliorated in the both treatment groups. It was accompanied by suppression of local endothelin-1 and renin mRNA expressions. Conclusions: Renal sympathetic denervation ameliorated progression of both myocardial and renal damages in the hypertensive rats, independent of blood pressure. The overall effects were similar with those of chronic β receptor blockade having the effects on heart rate and α adrenergic receptors’ expression. The underlying mechanism may be associated with preservation of myocardial sympathetic-nervous system and renal protection.
The Weekly Infusion of Bortezomib Reduces Peripheral Neuropathy.
Authors: Francesca Gay, Sara Bringhen, Mariella Genuardi, Davide Rossi, Roberto Ria, Alessandra Romano, Felicetto Ferrara, Nicola Di Renzo, Alida Dominietto, Alessandro Andriani, Rita Rizzi, Roberto Vallone, Giuseppe Mele, Sergio Storti, Luigi Podda, Gabriele Aitoro, Vincenzo Mettivier, Ombretta Annibali, Fausto Rossini, Patrizia Gentilini, Vincenzo Pavone, Nicola Giuliani, Anna Maria Rauco, Anna Baraldi, Antonio Capaldi, Filippo Gherlinzoni, Gianluca Gaidano, Mario Boccadoro, Antonio Palumbo
Journal: Blood (2009)
A Multicenter Phase I/II Trial of the Combination of Imatinib Mesylate with Mitoxantrone/Etoposide and Cytarabine in Patients with CML in Myeloid Blast Crisis: A Trend to a Longer Survival in Patients Receiving More Aggressive Treatment Schedules.
Authors: Stefan Fruehauf, Julian Topaly, Eike C. Buss, Thomas Fischer, Bertold Emmerich, Harald Gschaidmeier, Rudiger Hehlmann, Andreas Hochhaus
Journal: Blood (2004)
183. Developing Strategies To Improve the Current Clinical Vector AAV1-CB-AAT for Alpha-One Antitrypsin Deficiency
Authors: Florie Borel, Sourav Choudhury, George Aslanidi, Lina Song, Evren Kocabas, Huaming Sun, Qiushi Tang, Arun Srivastava, Kathryn Wagner, Miguel Esteves, Terence Flotte, Christian Mueller
Journal: Molecular Therapy (2015)

Alpha-one antitrypsin deficiency (AATD) is a genetic disorder that causes defective production of alpha-one antitrypsin (AAT), leading to decreased AAT activity in the blood and lungs, and deposition of excessive mutant Z-AAT protein in liver cells. There are several forms and degrees of deficiency, principally depending on whether the patient has one or two copies of the affected gene. Approximately 4% of the North American and Northern European populations possess at least one copy of a mutant allele. The current standard of care is protein replacement by frequent infusions, but gene replacement therapy could provide long-term correction of the serum levels after a one-time treatment only, which would offer a significant improvement in the quality of life of the patients. Towards this goal, a recent clinical trial tested injecting recombinant adeno-associated virus serotype 1 expressing M-AAT intramuscularly. However the therapeutic AAT serum threshold of 11μμM was not reached. Future efforts to achieve therapeutic levels will revolve around dose escalation and more efficient physical delivery. While the next trial may achieve therapeutic levels with the current AAV1-CB-AAT vector, it is worth further optimizing as it may result in a more efficient vector requiring a lower dose to achieve therapeutic levels. Achieving therapy with a lower dose has substantial benefits in the long run in terms of cost of production and more importantly potential immune responses to capsid. The current AAV1-CB-AAT gene therapy vector will be optimized through four independent strategies hypothetically leading to an increase of alpha-one antitrypsin serum levels in mice: 1) replacement of the secretion signal by secretion signals from other human secreted proteins, 2) modification of the AAV capsid either by triple tyrosine mutation or DNA shuffling, 3) optimization of the transgene to create self-complementary vectors with a codon-optimized AAT sequence, 4) addition of a hepatocyte-specific cis-regulatory module allowing recruitment of liver-specific transcription factors. In vivo data will be presented for each strategy. Future work will combine the validated candidates into a single vector for further evaluation; the use of this optimized vector may translate into a therapeutic effect for the AATD patients.
Abstract 2217: Prognostic and predictive values of CD68+ macrophage and aberrant expression of cathepsin L, IL-12, CTL4A genes in classic Hodgkin's lymphoma
Authors: Abdel-Rahman N. Zekri, Abeer A. Bahnassy, Ahmad E-S El-Bastawisi, Osama Hammad, Nasr M. Ali, John E. Diks, Hend F. Yousif
Journal: Cancer Research (2015)

Abstract Background: Despite advances in the treatment of classic Hodgkin lymphoma (CHL), current therapies fail to cure 10%-15% of patients, and a similar proportion of patients may be over treated, resulting in both short-term and long-term treatment-related complications. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on international prognostic score. Patients and Methods: CD 68 protein and RNA expression were assessed in 81 classic Hodgkin's lymphoma patients from Egypt by immunohistochemistry and Quantitative real time PCR (Q-RTP) respectively. Then CD 68 positive and CD 68 negative cases where profiled using the SABioscience array (Qiagen). Genetic aberrations were correlated to standard prognostic factors, patients response to the treatment, progression free and overall survival (PFS, OS) rates. Results: Increased CD68 protein and RNA expression were detected in 70.3% and 53.1% of the cases, respectively. Increased CD68 protein associated significantly with old age &amp;gt;40 (p = 0.035), advanced stage (p = 0.007), and poor response to treatment (DP/SD, p = 0.001). CD68 RNA expression significantly associated with age (p = 0.035), and poor response to treatment (DP/SD, p = 0.001). CD68+ positive patients, showed high expression of cathepsin L, IL-12, ATXN2L, CTL4A and MMP11. The 5 years OS correlated significantly with CD68, IL-12, MMP11 and CTL4A-RNA expression (p&amp;lt; 0.001) as well as with age (p&amp;lt;0.001) and stage (p&amp;lt;0.001). The 5 years PFS correlated significantly with age (p = 0.003), stage (p = 0.012), CD68 protein and RNA expression (p&amp;lt; 0.001) as well as with cathepsin L, IL-12, CTL4A and MMP11 (p&amp;lt;0.01). CD68 protein expression significantly correlated with 2 years OS (p&amp;lt; 0.001). Conclusions: in classic Hodgkin's lymphoma, CD68+ macrophage and aberrant expression of cathepsin L, IL-12, CTL4A and MMP11 provide sensitive biomarkers that can accurately predict patients response to treatment and survival with high accuracy. Citation Format: Abdel-Rahman N. Zekri, Abeer A. Bahnassy, Ahmad E-S El-Bastawisi, Osama Hammad, Nasr M. Ali, John E. Diks, Hend F. Yousif. Prognostic and predictive values of CD68+ macrophage and aberrant expression of cathepsin L, IL-12, CTL4A genes in classic Hodgkin's lymphoma. [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 2217. doi:10.1158/1538-7445.AM2015-2217
Compliance with calcium and vitamin D use in patients treated with zoledronic acid.
Authors: A. G. Ayoola, A. Singleton, H. A. Harvey
Journal: Journal of Clinical Oncology (2011)

e19691 Background: Zoledronic acid is a bisphosphonate indicated for metastatic skeletal related disease associated with multiple myeloma and solid tumors. There is a potential for severe and symptomatic hypocalcaemia with the use of this agent. Current recommendations include administration of vitamin D and calcium with zoledronic acid. The compliance with this recommendation is currently unknown. Methods: We reviewed the medical records of 440 patients diagnosed with metastatic skeletal related disease associated with both solid malignancy and multiple myeloma treated with zoledronic acid at Penn State Cancer Institute, Hershey, PA from January 2001 to June 2010. Twenty-two patients were excluded from the analysis due to insufficient data. Results: Of the 416 patients analyzed, 409 (98.3 %) had a solid malignancy and 7 (1.65%) had multiple myeloma. Thirty-one percent had lung cancer, 30% breast cancer, 15% prostate cancer, 5% renal cancer, 5% endocrine cancer, and other 12.35 % had miscellaneous cancers. The compliance with calcium and vitamin D supplements was 17.8% for solid tumors and 14.3% for multiple myeloma. The highest compliance was in patients with breast cancer (29%). Conclusions: We were surprised to discover that the compliance with the use of vitamin D and calcium as supplements in patients treated with zoledronic acid is low in this single institution retrospective study. We suspect that this omission might be widespread practice. Further study is required to determine the extent of symptomatic hypocalcemia following noncompliance with this recommendation. We recommend that this aspect of compliance should be evaluated with denosumab.
Limitations on obtaining biomarker’s expression levels in patients with non-small cell lung cancer (NSCLC): Are there any differences between surgical biopsies, bronchoscopy, or core biopsies?
Authors: R. E. Ochoa, J. C. Villasboas, E. S. Santos, J. E. Gomez, K. Danenberg, L. E. Raez
Journal: Journal of Clinical Oncology (2011)

e21039 Background: EGFR mutation is predictive for chemotherapy and TKI response in patients (pts) with NSCLC. ERCC1, RRM1 and TS might also have predictive value. The main difficulty in evaluating these tumor biomarkers (BM) is related to the amount of tissue available. It is unclear whether any specific biopsy technique improves the detection of these BM. We looked into the differences in obtaining successful BM expression in pts with NSCLC depending on biopsy technique used as diagnostic tool. Methods: We did a cross-sectional study of pts with NSCLC with tissue available for evaluation of BM expression. The main endpoint was to evaluate expression levels of ERCC1, RRM1, TS, and the presence of EGFR and K-ras mutation, and compare current biopsy techniques to achieve this goal. BM data was obtained from tumor samples by using ResponseDx test: RNA expression of ERCC1, TS, and RRM1 was analyzed by RT-PCR and PCR analysis of DNA was used to determine K-ras and EGFR mutation status. Statistical analysis was done by Fisher’s exact test. Results: 67 patients with NSCLC seen at Sylvester Cancer Center between March 2009 and December 2010 had tumor samples evaluated for BM expression levels. 21 (31%) of the samples didn’t yield enough tissue for BM evaluation. 30 (44%) didn’t have enough tissue to allow measurement of at least one BM. 16 pts (23.8%) underwent biopsy via bronchoscopy, 13 (19.4%) by FNA, 14 (20.9%) by CT-guided biopsy, and 24 (35.8%) via surgery. Surgical biopsy and bronchoscopy had the highest chance of obtaining adequate tissue for BM detection (62.5%), FNA had 46.2% chance, and CT-guided biopsy the lowest (42.8%). No statistical difference was seen among the techniques used (p=0.20). Conclusions: The detection of BM in pts with NSCLC was limited in more than a third of the patients. There was no statistical difference between different biopsy methods regarding the yield of sufficient tissue for testing. Evaluating patients’ tumor for genetic mutations and other markers is becoming standard of care in the initial therapeutic decision making of pts with NSCLC. More studies are needed to improve the chances of adequate tissue for testing.
Improved Outcome by Addition of Lomustine (CCNU) to Idarubicin and Cytarabine in Elderly Patients with De Novo Acute Myeloid Leukemia. A Report from the GOELAMS Group
Authors: Arnaud Pigneux, Francis Witz, Mathieu Sauvezie, Marie-Christine Bene, Isabelle Luquet, Mathilde hunault-Berger, Christian Recher, Norbert Vey, Bruno Lioure, Chantal Himberlin, Martine Escoffre-Barbe, Christian Berthou, Severine Lissandre, Nathalie Fegueux, Jean-Yves Cahn, Eric Jourdan, Didier Bouscary, Francois Dreyfus, Josy M. Reiffers, Noel Milpied, Jean-Luc Harousseau, Norbert Ifrah
Journal: Blood (2008)
Development of a multidimensional assessment tool for uraemic pruritus: Uraemic Pruritus in Dialysis Patients (UP-Dial)
Authors: S. Nochaiwong, C. Ruengorn, R. Awiphan, S. Panyathong, K. Noppakun, W. Chongruksut, S. Chiewchanvit
Journal: British Journal of Dermatology (2016)

Dialysis patients with uraemic pruritus (UP) have significantly impaired quality of life. To assess the therapeutic effect of UP treatments, a well‐validated comprehensive and multidimensional instrument needed to be established. To develop and validate a multidimensional scale assessing UP in patients on dialysis: the Uraemic Pruritus in Dialysis Patients (UP‐Dial). The development and validation of the UP‐Dial instrument were conducted in four phases: (i) item generation, (ii) development of a pilot questionnaire, (iii) refinement of the questionnaire with patient recruitment and (iv) psychometric validation. Participants completed the UP‐Dial, the visual analogue scale (VAS) of UP, the Dermatology Life Quality Index (DLQI), the Kidney Disease Quality of Life‐36 (KDQOL‐36), the Pittsburgh Sleep Quality Index (PSQI) and the Beck Depression Inventory (BDI) between 15 May 2012 and 30 November 2015. The 27‐item pilot UP‐Dial was generated, with 168 participants completing the pilot scale. After factor analysis was performed, the final 14‐item UP‐Dial encompassed three domains: signs and symptoms, psychosocial, and sleep. Face and content validity were satisfied through the item generation process and expert review. Psychometric analysis demonstrated that the UP‐Dial had good convergent and discriminant validity. The UP‐Dial was significantly correlated [Spearman rank coefficient, 95% confidence interval (CI)] with the VAS‐UP (0·76, 0·69–0·83), DLQI (0·78, 0·71–0·85), KDQOL‐36 (−0·86, −0·91 to −0·81), PSQI (0·85, 0·80–0·89) and BDI (0·70, 0·61–0·79). The UP‐Dial revealed excellent internal consistency (Cronbach's α 0·90, 95% CI 0·87–0·92) and reproducibility (intraclass correlation 0·95, 95% CI 0·90–0·98). The UP‐Dial is valid and reliable for assessing UP among patients on dialysis. Future research should focus on the cross‐cultural adaptation and translation of the scale to other languages.
544. Comparison of AAV Serotype2 Transduction by Various Delivery Routes to the Mouse Eye
Authors: Kenton T. Woodard, Melisa Vance, Brian Gilger, R. Jude Samulski, Matthew Hirsch
Journal: Molecular Therapy (2016)

AAV gene therapy has demonstrated success for the treatment of several ocular diseases with the tropism and efficiency of AAV retinal transduction being a function of the route of administration. Subretinal injection has been the primary route to deliver AAV to the retina but this injection route carries surgical complications and transduction remains localized to the area of retinal detachment. Despite the use of suprachoroidal injections for ocular drug delivery in large animal models, this route has not been comprehensively compared to AAV vector transduction following other administration routes in mice. AAV serotype 2 (AAV2) was used to deliver a self-complementary CMV-GFP reporter cassette via intrastromal, intracameral, intravitreal, subretinal, or suprachoroidal injections. These injections were validated by fundoscopy and optical coherence tomography at the time of injection. Transduction was assessed six weeks later by fundoscopy and whole globes were evaluated for histology. Transduction of the stroma, ciliary body, retinal ganglion cells, outer retina, and retinal pigment epithelium could be seen in the various routes of delivery to the eye. In particular, the transduction of multiple retinal layers throughout the retina without the damage of retinal detachment and widespread distribution makes suprachoroidal injections a better delivery route than to subretinal injection.
266. G-Force Loading of Virus Vectors into Vesicles for Enhanced Gene Therapy Vehicles
Authors: Zachary Fitzpatrick, Andreas Maus, Bence Gyorgy, Dakai Mu, Krisztian Csomos, Jolan E. Walter, Casey A. Maguire
Journal: Molecular Therapy (2015)

Adeno-associated virus (AAV) vectors have shown remarkable efficiency in a number of preclinical models of disease in several organs including the eye, brain, muscle, heart, and liver. A major limitation to long term transduction, especially via the systemic route, is pre-existing immunity (humoral and cell-mediated) as well as the high vector load required to achieve sufficient levels of gene expression in the desired organ. Natural nanoparticles released from all cells, called extracellular vesicles (EVs), may have utility in creating better AAV vectors for human gene therapy. We have previously shown that harvesting AAV vectors from the media of 293T producer cells contains AAV vectors endogenously associated with EVs (called ev-AAV, aka vexosomes). We have gone on to demonstrate that 293T-derived ev-AAV can evade neutralizing anti-AAV antibodies and greatly increase transduction in mice. An alternative strategy would be to load purified AAV vectors into separately purified EVs. This would have the benefit of using EVs from a variety of cellular sources with desired biological activity and also to use donor-derived autologous EVs. Here we demonstrate a simple method for loading EVs with AAV vectors using high speed centrifugation forces. Iodixanol density gradient-purified AAV was mixed with conditioned media containing EVs from 293T cells and also primary human peripheral blood mononuclear cells (PBMCs) and then ultracentrifuged to co-pellet EVs and AAV. The pellet was resuspended in media and used in transduction assays and anti-AAV antibody neutralization assays. Strikingly we found that this process bestowed greatly enhanced transduction of cells in culture (36-fold) as well as resistance to neutralizing anti-AAV antibodies. To demonstrate that EVs were essential to this enhancement, we mixed AAV with plain media (no EVs) or depleted conditioned media of EVs before addition of AAV using either Triton-X-100 EV lysis or ultracentrifugation. In all cases there was a large decrease in the transduction efficiency and antibody evasion compared to conditioned EV media mixed with AAV. Together these data suggest that g-force loading of AAV into EVs represents a promising method to increase performance of the vector. We will continue to optimize the protocol and test the gene delivery functions in vivo.
Abstract 3633: Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation
Authors: Aaron Wilson, Vasily A. Yakovlev
Journal: Cancer Research (2015)

Abstract Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DNA double-strand breaks (DSBs) by the cellular replication and/or transcription machinery. Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair (HRR) of DNA DSB. In BRCA-positive cells, DSBs are repaired by HRR, but they cannot be properly repaired in BRCA-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. The role of PARP1 in the DNA damage response promoted the development of PARP inhibitors (PARPi) as chemo- and radio-sensitizers for the treatment of cancers harboring mutations in the BRCA genes. However, inherited BRCA1 or BRCA2 mutations account for 5-10% of breast cancers and 10-15% of ovarian cancers. Hence, a low frequency of BRCA1 loss in non-hereditary tumors can limit the clinical use of this approach. Our recent work revealed significant down-regulation of BRCA1 gene expression by nitric oxide donors (NO-d) (Yakovlev, 2013). Hence, we assumed that combination of NO-d with PARP inhibitors could be effective in sensitization of the BRCA1-positive tumors to DNA-damaging therapy. We identified the optimal concentrations of PARPi ABT-888 at 20μM and NO-d SNAP at 200μM, which don't affect cell survival, but effectively block PARP1 activity or BRCA1 expression accordingly. Next, cancer cell lines were pretreated with ABT-888 or SNAP, or with they combination and irradiated. Survival curves were determined by clonogenic assay. Our preliminary data demonstrates significant radiosensitization when combining an NO-d with a PARPi in BRCA1 positive tumor cell lines (Table 1). We plan to test this drug combination on the additional cancer cell lines and on animal models for sensitization to ionizing radiation and to the different chemotherapeutic agents. Table 1.Clonogenic assay for A-549 and MDA-MB-231 cell lines: survival fraction.IR (Gy)02468A-549Control1.00±0.0380.55±0.0450.23±0.0360.09±0.0070.0242±0.004ABT-8881.00±0.0650.49±0.0310.18±0.0350.05±0.0040.0076±0.001SNAP0.97±0.0850.43±0.0450.16±0.0330.04±0.0080.0091±0.002ABT-888 + SNAP0.71±0.0750.24±0.0420.05±0.0070.01±0.0020.0014±0.0003MDA-MB-231Control1.00±0.0630.44±0.0380.15±0.0270.039±0.0070.0078±0.0007ABT-8880.85±0.0520.28±0.0170.07±0.0090.012±0.0020.0015±0.0005SNAP1.03±0.0380.3±0.0430.10±0.0080.020±0.0040.0034±0.0007ABT-888 + SNAP0.49±0.0660.12±0.0170.02±0.0070.002±0.00040.00013±0.0001 Citation Format: Aaron Wilson, Vasily A. Yakovlev. Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation. [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 3633. doi:10.1158/1538-7445.AM2015-3633