tbuckley/cabot-search huggingface dataset:
30. Phase II Clinical Trial of Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA-SCID) Using a γ-Retroviral Vector
Authors: Kit L. Shaw, Elizabeth Garabedian, Rob Sokolic, Provaboti Barman, Alejandra Davila, Christopher Silvin, Satiro de Oliveira, Ami J. Shah, Dayna Terrazas, Denise Carbonaro, Sabine Geiger, Suparna Mishra, Aaron Cooper, Monika Smogorzewska, Jayashree Jagadeesh, Michael S. Hershfield, Alan Wayne, Gay M. Crooks, Theodore Moore, Fabio Candotti, Donald B. Kohn
Journal: Molecular Therapy (2015)

We report follow-up of subjects treated in a Phase II study of gene therapy for ADA-SCID. Between 2009 and 2012, ten ADA-deficient SCID patients were treated by γ-retroviral-mediated gene transfer (MND-ADA) to their bone marrow CD34+ cells. The subjects were given non-myeloablative chemotherapy (busulfan @ 90 mg/m2) and were withdrawn from PEG-ADA enzyme replacement therapy (ERT) prior to infusion of autologous gene-modified cells. Subject age at the time of treatment ranged from 3 months to 15 years (median = 11.5 months). Follow-up times range from 2 to 5 years. All but one subject, who was 15-years old at the time of treatment, remain off PEG-ADA ERT with immune reconstitution that reached maximal level between 6 and 12 months after transplant and was maintained thereafter. Vector marking in peripheral blood cells remained consistently detectable (> 0.1 copy/PBMC and ≥ 0.003 copy/granulocyte) at 2 years and later after transplant in subjects who discontinued ERT. These subjects also had PBMC ADA enzymatic activity in the normal range and red blood cell deoxynucleotide levels below 10%. Three subjects have discontinued intravenous immunoglobulin; five subjects have discontinued prophylactic antibiotics. All subjects have polyclonal gene marking with no sign of lymphoproliferative disease. The subjects remain in good health without infections or other complications.
49. Minimum Effective Dose of Liver-Targeted Gene Therapy for Pompe Disease Reduced 10-Fold from Prior Estimates
Authors: Sang-oh Han, Benjamin Amson, Korie Busch, Giuseppe Ronzitti, Songtao Li, Federico Mingozzi, Dwight D. Koeberl
Journal: Molecular Therapy (2016)

Pompe disease (glycogen storage disease type II; acid maltase deficiency) is a devastating myopathy resulting from acid alpha-glucosidase (GAA) deficiency in striated and smooth muscle. Despite the availability of enzyme replacement therapy (ERT) with recombinant human GAA, many patients have poor outcomes including mortality. ERT has increased survival rates, improved hypotonia, and resolved heart involvement in patients with Pompe disease. However ERT is limited by the short half-life of GAA and the formation of antibody responses that reduced its clinical benefits. The present study compared the efficacy of ERT against an adeno-associated viral (AAV) vector containing a liver-specific promoter, AAV2/8-LSPhGAApA. We hypothesized that liver-specific expression of GAA with AAV2/8-LSPhGAA would suppress the antibody response, continually express GAA, and improve efficacy in comparison with ERT. Preclinical experiments with Pompe disease therapies demonstrated that a very low amount of AAV2/8-LSPhGAApA, 2×1010 vector particles (vp), equivalent to 8×1011 vp/kg body weight, was as effective as long-term ERT. Therefore, we evaluated the biochemical efficacy of 3 lower dosages of AAV2/8-LSPhGAA in GAA knockout (KO) mice, reduced to as low as 2×1010 vp/kg, either alone or in combination with ERT. Biochemical correction in GAA-KO mice was evaluated 8 weeks following vector administration. The minimum effective dose (MED) was at least 10-fold lower than previously estimated, because 8×1010 vp/kg significantly reduced glycogen content in the striated muscle of GAA-KO mice. This MED of AAV2/8-LSPhGAA significantly increased GAA activity in liver (p<0.01), in comparison with untreated GAA-KO mice. Importantly, the MED significantly reduced the glycogen content of heart (p<0.01; Fig. A), and diaphragm (p<0.01; Fig. B), which demonstrated that the glycogen storage in muscle associated with Pompe disease was substantially cross-corrected by GAA secretion from liver accompanied by receptor-mediated uptake in striated muscle. Glycogen clearance, or reduction in comparison with no treatment, was 36% in heart, and 35% in diaphragm. Furthermore, administering ERT by itself had no significant effect on the glycogen content of quadriceps, but ERT following administration of the MED of AAV2/8-LSPhGAA significantly reduced glycogen content of quadriceps (p<0.05; Fig. C) by 38%, indicating that gene therapy with AAV2/8-LSPhGAA made ERT more effective. Vector dose correlated inversely with anti-GAA antibody formation, confirming that immune tolerance to GAA was critical to the efficacy from AAV2/8-LSPhGAApA. In conclusion, the MED for AAV2/8-LSPhGAA has been estimated at least 10-fold lower than previous data suggested, and this dosage would be acceptable as a starting dose for a Phase I clinical trial of gene therapy in Pompe disease.
Immunological Recovery after Nonmyeloablative Transplant: A Prospective Study of 24 Patients Treated in a Single Center.
Authors: Dominique Bron, Van Hyunh, Virginie Dewilde, Jalil Bennani, Philippe Lewalle, Phuong Huynh, Rita Leroy, Patrick Crombez, Louisette Debusscher, Walter Feremans, Michel Bernier, Philippe Martiat
Journal: Blood (2004)
Phase II study of RCHOP with pegylated liposomal doxorubicin (DRCOP) for patients older than age 60 with untreated diffuse large B-cell lymphoma (DLBCL).
Authors: M. A. Rodriguez, J. Durand, A. B. Astrow, M. J. Bury, M. A. Fanale, F. B. Hagemeister, X. Huang, P. McLaughlin, S. S. Neelapu, B. Pro, L. W. Kwak, L. Fayad, J. E. Romaguera, A. Younes, M. Fisch
Journal: Journal of Clinical Oncology (2011)

8053 Background: DLBCL is a common lymphoma of older adults, and a potentially curable disorder with the regimen RCHOP (Coiffier, et.al. NEJM,2002). Doxorubicin, a key drug in the regimen, has risk for cardiotoxicity, and thus of concern in older patients (pts) with higher incidence of cardiovascular (CV) disease. In breast cancer pts pegylated liposomal doxorubicin (D) has shown greater cardiac safety and similar efficacy to doxorubicin. We thus replaced doxorubicin with D in RCHOP (DRCOP). Methods: The regimen is: rituximab 375 mg/m2 IV day (d) 1; D 40 mg/m2 IV d 1; cyclophosphamide 750 mg/m2 IV d 1; vincristine 2 mg IV d 1 total dose; prednisone 100 mg/d p.o. d 1-5. Eligibility criteria were: > 60 years of age; untreated confirmed DLBCL (no discordant histology); Ann Arbor stage II-IV; baseline LVEF 50%. CV disease was permitted, if symptoms controlled, but consult at baseline by Cardiologist and at follow-up required. Troponin and brain natriuretic peptide (BNP) levels were monitored. Granulocyte growth factor support recommended (not required). Results: 80 pts total were enrolled on study; 79 were eligible and evaluable for response and toxicity. Characteristics of pts: age 61-94 years (median 71); 41 female. All had at least one cardiac risk factor. Responses were: 55 CR (69%); 14 PR. (17%) At a median follow-up of 2.7 years, 62 are alive (77%), with 78% progression free survival. There were 7 grade 3 adverse cardiac events: 1 drop in LVEF; 4 atrial arrhythmias (reversed); 1 hypotension (reversed); 1 chest pain (reversed). Troponin and BNP changes did not correlate with cardiac events. Other grade 3-4 non-hematologic events: 3 hand-foot syndrome; 4 fatigue; 2 DVT; 2 neuropathy. Only one death occurred on study due to pneumonia, non-neutropenic. The most common grade 3-4 toxicity events were hematologic. Conclusions: DRCOP is an active regimen. In this study of older pts with DLBCL, only one pt had drop in LVEF below normal. Other cardiac events were associated with underlying cardiac conditions, and were reversible. Liposomal doxorubicin should be considered in older patients. Comanagement by a Cardiologist during chemotherapy would be recommended.
PTU-072 Screening, referral practice and management of hepatitis B and C in primary care: a survey of general practitioners: Abstract PTU-072
Authors: K M Taylor, A Narbey, A McNair, M Foxton
Journal: Gut (2010)

<h3>Introduction</h3> In order to optimise our viral hepatitis service, we wished to assess the knowledge and referral practice of primary care physicians in our local area. General practitioners (GPs) have a vital role in the identification of patients who require screening for hepatitis B (HBV) and C (HCV), referring appropriately, and in supporting treatment in conjunction with the hepatitis clinic. The area around QEH has a prevalence rate of 3% positive HBsAg in the antenatal population and ∼100 new positive HCV antibody tests per year. <h3>Aim</h3> to assess GP knowledge of and attitudes to HBV and HCV with respect to transmission, screening, serological tests, referral to secondary care and treatment. <h3>Methods</h3> A survey containing 32 questions was sent to GPs within our catchment area. Where there was no response after several months, the questionnaire was reissued. <h3>Results</h3> 45/161 (28%) questionnaires were completed and returned. Demographics: Mean age 46 years (20f; in general practice 14 years (1–35); 96% of practices had &gt;5000 patients. 90% of respondents would attend an educational seminar on viral hepatitis. Only 36% of GPs thought all patients with chronic HBV should be managed in secondary care, compared with 59% for HCV. 8/45 (17%) knew how to correctly screen for HBV and 30/45 (67%) knew how to assess response to HBV vaccination. Two scenarios for HBV were presented: a pregnant woman found to be surface antigen positive on screening; and a Nigerian man known to be surface antigen positive, who had an alanine aminotransferase (ALT) four times the upper limit of normal. Only 24/45 and 16/45, respectively, would refer these patients to a specialist. Further scenarios for HCV: an asymptomatic woman with a reactive HCV antibody at blood donation and normal ALT; and an asymptomatic man with a reactive HCV antibody and an ALT five times the upper limit of normal, yielded 21/45 and 29/45 potential referrals, respectively. <h3>Conclusion</h3> Without a basic understanding of chronic viral hepatitis, including a knowledge of who and how to screen for HBV and HCV, and when to refer, a significant proportion of patients will not receive appropriate treatment. In the longer term this will result in an increased incidence of the complications of HBV and HCV with important implications for hepatology services. Improved training and education are required for general practitioners and hospitals should provide clear management guidelines to local GPs.
Abstract 3562: Protein palmitoylation in breast cancer: DHHC5 palmitoyltransferase as a potential therapeutic target
Authors: Hui Tian, Xiaoxia Qi, Kenneth Huffman, John Minna, Sandra L. Hofmann
Journal: Cancer Research (2015)

Abstract Protein S-palmitoylation is a widespread and dynamic post-translational modification that regulates protein-membrane interactions, protein-protein interactions, and protein stability. S-palmitoylation is catalyzed by members of a family of 23 palmitoyl acyl transferases, termed the DHHC family due to the presence of a common catalytic motif. The role of protein palmitoylation in cancer is largely unexplored. In our previous study, we have shown that DHHC5 palmitoyltransferase supports the growth of non-small cell lung cancer. To further investigate the role of DHHC5 in cancer, we expanded our study to include breast cancer cell lines. Stable knockdowns of DHHC5 were undertaken in 8 breast cancer cell lines (including 4 “triple-negative” breast cancer lines) as well as in two normal human mammary epithelial cell lines (HMECs) using lentiviral shRNAs. The protein levels of DHHC5 were analyzed by immunoblotting, which all showed efficient knockdown. Cell proliferation and anchorage-dependent/ independent colony formation assays indicated that DHHC5 knockdown led to cell growth arrest and decreased cell clonogenicity in most of the tested breast cancer cell lines in vitro, but not in the HMECs. BT-549, SkBr3 and T-47D cell lines were particularly dependent on DHHC5 expression, and rescue experiments involving ectopic plasmid-driven DHHC5 and its catalytic mutant DHHS expression are in progress. In vivo tumor formation assays will be carried out by injecting MCF-7 and T-47D control cells and DHHC5 stable knockdown cells as well as rescued cells subcutaneously into NOD/SCID mice. Tumor xenograft formation will be measured. As DHHC5 function is needed for optimal breast cancer cell growth, it will be important to identify physiologically relevant substrates in order to develop inhibitors of DHHC5 function. Future plans include microarray and protein kinase array analysis to identify possible signaling pathways in which DHHC5 may be involved, as well as palmitoyl-protein profiling of control and knockdown DHHC5 cell lines by mass spectrometry. Citation Format: Hui Tian, Xiaoxia Qi, Kenneth Huffman, John Minna, Sandra L. Hofmann. Protein palmitoylation in breast cancer: DHHC5 palmitoyltransferase as a potential therapeutic target. [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 3562. doi:10.1158/1538-7445.AM2015-3562
Severe Myelodysplasia with Monosomy 7 Developing during Imatinib Treatment of Philadelphia-Positive Chronic Myeloid Leukemia: Two Cases Evolving with Different Outcome.
Authors: José-Tomás Navarro, Evarist Feliu, Javier Grau, Dolors Colomer, Blanca Espinet, Isabel Granada, Blanca Xicoy, Elisa Orna, Albert Oriol, Natalia Lloveras, Jordi Junca, Josep-Maria Ribera, Fuensanta Milla
Journal: Blood (2005)
Abstract 2646: Targeting cancer stem cell pathways with cell-permeable peptide inhibitors
Authors: Verena Arndt, Annette Friebe, Elena Meuser, Katharina Ross, Franziska Agerer, Carmen Schulten-Schulz, Jens Waak, Daniel Friedrich, Hanjo Hennemann, Jörg Vollmer
Journal: Cancer Research (2015)

Abstract Direct targeting of several important cancer pathways has so far proved challenging, owing to the lack of pathway-specific targets that can be accessed by conventional small molecule drugs or therapeutic antibodies. Nexigen develops and advances peptide-based cancer therapeutics, a new class of drugs that functionally modulate currently undruggable pathways by targeting intracellular protein-protein-interactions. One of these undruggable pathways, the Wnt signaling cascade, has been identified as a key pathway in cancer stem cells maintenance. Targeting oncongenic Wnt signaling therefore holds great promise for tackling not only tumor growth but also disease relapse, metastasis and drug resistance. Using our proprietary next generation peptide screening system, we could identify cell-permeable peptides that efficiently inhibit the Wnt pathway through a specific interaction with a key component of intracellular signaling. Our most advanced preclinical candidate has nanomolar target affinity and significantly reduces the expression of Wnt target genes in triple-negative MDA-MB-231 breast cancer cells. The further functional analysis of the peptide in various cancer cell lines revealed a dose-dependent inhibition of cell migration, invasion, proliferation, and the cancer stem cell phenotype. The siRNA-mediated knock-down of the target protein or the inhibition of the Wnt pathway recapitulated the inhibitory peptide effect in these assays. Most importantly, we observed a significant suppression of primary tumor growth, tumor cell self-renewal and a reduction of metastatic potential after treatment in different xenograft models. In summary, our data suggest that our Wnt pathway peptide inhibitor could be a promising new drug candidate for the treatment of cancer stem cells in a broad diversity of cancers. Citation Format: Verena Arndt, Annette Friebe, Elena Meuser, Katharina Ross, Franziska Agerer, Carmen Schulten-Schulz, Jens Waak, Daniel Friedrich, Hanjo Hennemann, Jörg Vollmer. Targeting cancer stem cell pathways with cell-permeable peptide inhibitors. [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 2646. doi:10.1158/1538-7445.AM2015-2646
Eculizumab (ECU) Significantly Improves Health-Related Quality of Life (HRQoL) in Patients with Atypical Hemolytic Uremic Syndrome (aHUS)
Authors: Petra Muus, Christoph Licht, Tim H. J. Goodship, Larry Greenbaum, Camille L Bedrosian, Chantal Loirat, Christophe Legendre
Journal: Blood (2011)
Peripheral Blood Cells from Multiple Myeloma Patients Show Increased Osteoclast and Decreased Osteoblast Gene Expression.
Authors: Melinda S. Gordon, Ariana M. Berenson, Charles B. Drucker, Matthew Katz, Hee Jin Lee, Richard A. Campbell, Haiming Chen, Howard S. Yeh, Benjamin Bonavida, Jonathan Said, James R. Berenson
Journal: Blood (2005)
Hepatic Veno-Occlusive Disease in Children after Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, and Outcome
Authors: Soo Hyun Lee, Mi Mi Kwon, Young Joo Kwon, Hyeon Jin Park, Byung-Kiu Park, Jeong A. Park, Ho Joon Im, Jong Jin Seo, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Hyoung Jin Kang, Hee Young Shin, Hyo Seop Ahn
Journal: Blood (2008)
Incidence of Late Chronic Anemia in Newly Diagnosed Patients with Chronic Myelogenous Leukemia Responsive to Imatinib
Authors: Paola Volpicelli, Roberto Latagliata, Massimo Breccia, Federico Vozella, Paola Finsinger, Ida Carmosino, Giuseppina Loglisci, Michelina Santopietro, Adriano Salaroli, Daniela Diverio, Marco Mancini, Agostino Tafuri, Giuliana Alimena
Journal: Blood (2012)
Resting energy expenditure in patients with metastatic colorectal cancer.
Authors: J. L. Gonzalez Vela, H. I. Novelo Huerta, Y. Cedillo Juarez, J. F. Gonzalez Guerrero, G. Garza Sepulveda, M. d. J. Ibarra Salas
Journal: Journal of Clinical Oncology (2011)

e21102 Background: Resting energy expenditure (REE) has been measured in patients with cancer with nonconclusive results. Studies have included heterogeneous populations with different primary cancers and stages of the disease. It has been postulated that REE is increased in patients with cancer and recently there is interest in energy consumption, metabolism and the genesis of cancer. This study is limited to patients with metastatic colorectal cancer. Methods: Informed consent and ethics institutional committee approval were obtained. Twenty patients with metastatic colorectal cancer were entered in the study from January 2009 to November 2010. Antropometric body measurements and indirect calorimetry were performed during their outpatient clinic visits. Patients were classified as hypermetabolic if they were 110% above their predicted REE (according to the Harris Benedict formula), Hypometabolic if they were under 9% of predicted, and normometabolic within 10% and 100% of predicted. Data were compared with a normal control group. SPSS software was used for statistical analysis. Results: 20 patients with a diagnosis of metastatic colorectal cancer 14 male and 6 female were included. Median age was 51 years, sites of metastases were liver 12 (60%), peritoneum 4 (20%), others 4 (20%). During the time of study 17 patients were on chemotherapy (85%), 2 were on radiotherapy (10%). Of the study group 11 patients (55%) were found to be hypermetabolic, 5 were normometabolic (25%), and 4 were hypometabolic. This did not differ significantly from the control group, where 40% of the patients were hypermetabolic. Analysis restricted to the patients with liver metastases 9 patients (81.8%) were found to be hypermetabolic as compared to 40% in the control group and statistically significant (p less than .05). There were no significant associations between patients in remission or with progressive disease with REE. Conclusions: There was a marked tendency towards hypermetabolism in patients with colorectal cancer with liver metastases as seen with this indirect calorimetry measurement. We did not find an increase in REE in the whole group as compared to the controls.
Novel rapid PCR for the detection of Ile491Phe rpoB mutation of Mycobacterium tuberculosis , a rifampicin-resistance-conferring mutation undetected by commercial assays
Authors: E. André, L. Goeminne, A. Colmant, P. Beckert, S. Niemann, M. Delmee
Journal: Clinical Microbiology and Infection (2016)

ObjectivesNeither the liquid medium-based Bactec MGIT, nor commercial molecular assays such as the Xpert MTB/RIF and the MTBDRplus V2.0 assays are capable of detecting up to 30% of rifampicin-resistant Mycobacterium tuberculosis strains in Swaziland because of the large proportion of the rpoB Ile491Phe mutations. In other countries, the frequency of this mutation is thought to be low.MethodsWe designed a real-time multiplex allele-specific PCR assay to identify the rpoB Ile491Phe mutation responsible for these undetected resistant M. tuberculosis strains.ResultsThe technique showed 100% similarity with rpoB sequencing on a panel of 78 strains from Swaziland.ConclusionsWe propose that the detection of the rpoB Ile491Phe rpoB mutation should complement commercial assays for the diagnosis of rifampicin-resistant M. tuberculosis in routine conditions, particularly in countries where this specific mutation is frequent. The technique proposed in this paper is adapted for most reference laboratories.
406. Development and Optimization of PSCA-Specific CAR T Cells for the Treatment of Bone Metastatic Prostate Cancer
Authors: Dileshni Tilakawardane, Ethan A. Gerdts, Anthony K. Park, Wen-Chung Chang, Sarah Wright, Christine Brown, Stephen J. Forman, Saul J. Priceman
Journal: Molecular Therapy (2016)

Prostate Cancer (PCa) is the third most common cancer type in the United States, with over 200,000 new cases projected to be diagnosed this year. In approximately 80% of PCa patients, tumor phenotype includes overexpression of prostate stem cell antigen, or PSCA. Furthermore, PSCA is expressed on nearly 100% of bone metastatic prostate cancers, making it an attractive immunotherapeutic target. We have genetically engineered T cells to express chimeric antigen receptors (CARs) which specifically target PSCA. Recent clinical trials with CARs targeting CD19 for B-cell malignancies have demonstrated impressive results, yet replicating this success with other antigen targets remains elusive. Immunotherapy against solid tumors poses a more difficult tumor challenge because of the immunosuppressive microenvironment that can significantly hinder CAR efficacy. Additionally, there have been instances of on-target, off-tumor toxicity due to low levels of antigen expression on normal tissue. In the current project we have modified various components of our CAR constructs to improve specificity and overall therapeutic efficacy. Through various in vitro functional assays and in vivo xenograft models, we have evaluated and optimized a PSCA-targeting CAR. We first compared two single-chain variable fragments with different paratopes. While both show comparable potency, one of the scFvs showed nonspecific activity against PSCA-negative tumor lines. Similarly, our data suggest that the 28ζ-costimulatory domain, regardless of linker length, also shows non-specific activation and killing of PSCA-negative tumor lines as compared to the 4-1BB costimulatory domain. Finally, we have demonstrated differences between long, middle, and short linker lengths in intracellular cytokine production, activation, and killing capacities in vitro and in vivo. By modifying both the ectodomain and intracellular region, we are able to improve the specificity and functionality of our PSCA-CARs, which is essential to developing effective immunotherapies for this advanced disease.
Re-Mineralization of Large Pelvic Lytic Lesions By CT Imaging in Patients with Multiple Myeloma: The Arkansas Experience
Authors: Meera Mohan, Rohan Samant, Larry J Suva, Corey O Montgomery, Daisy V. Alapat, Roy Morello, Frits van Rhee, Sarah Waheed, Sharmilan Thanendrarajan, Carolina Schinke, Christoph Heuck, Yogesh Jethava, Donald Johann, Bart Barlogie, Faith E Davies, Gareth J Morgan, Maurizio Zangari
Journal: Blood (2015)