tbuckley/cabot-search huggingface dataset:
Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study
Authors: Stacy W. Gray, Sarah E. Gollust, Deanna Alexis Carere, Clara A. Chen, Angel Cronin, Sarah S. Kalia, Huma Q. Rana, Mack T. Ruffin, Catharine Wang, J. Scott Roberts, Robert C. Green
Journal: Journal of Clinical Oncology (2017)

Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers' behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors.
359. Gene Transfer of the Na, K-ATPase beta1 Subunit and Occludin Using Electroporation Rescues Lipopolysaccaride (LPS)-Induced Acute Lung Injury
Authors: Xin Lin, Michael Barravecchia, David A. Dean
Journal: Molecular Therapy (2015)

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by acute respiratory failure and associated with diverse disorders. Gene therapy is a potentially powerful approach to treat ALI and ARDS through repair of alveolar epithelial function. We previously showed that electroporation-mediated gene transfer of the b1 subunit of the Na,K-ATPase to the lung not only increased alveolar fluid clearance, but also improved epithelium/endothelium barrier functions via up-regulation of tight junction proteins to provide partial treatment of lipopolysaccaride- (LPS-) injured lungs. To further investigate if we could improve treatment, we co-delivered plasmids expressing occludin, which is the one of major constituents of tight junctions located at the plasma membrane. Lung injury was induced 1 day before gene delivery by intratracheal administration of LPS (5 mg/kg) and assessed by wet-to-dry ratios, histological analysis, myeloperoxidase (MPO) measurement, and bronchoalveolar lavage (BAL) protein levels and cellularity. Delivery of b1-Na,K-ATPase and occludin alone or in combination using electroporation treated previously injured lungs in a mouse model, compared to the control plasmid pCDNA3. However, combined gene transfer of b1-Na,K-ATPase and occludin only provided similar treatment benefit to either gene delivery of b1-Na,K-ATPase or occludin alone although the expression of tight junction proteins had been increased. These results demonstrate that both b1-Na,K-ATPase and occludin regulate formation of tight junctions in severely injured lungs and thus may play a critical role in the treatment of ALI/ARDS. It indicates that epithelial or endothelial barrier functions may be involved in the treatment of ALI/ARDS.
Atorvastatin Therapy Restores Nitric Oxide-Dependent Vascular Responsiveness in Patients with Sickle Cell Disease.
Authors: Gregory J. Kato, Christian Hunter, Lori Hunter, Andre Dejam, Roberto Machado, Kyle Mack, Jose Villagra, James Nichols, Wynona Coles, Vandana Sachdev, Richard Cannon, Mark T. Gladwin
Journal: Blood (2004)
Abstract 4855: DBGC: database of gastric cancer
Authors: Yingyan Yu
Journal: Cancer Research (2015)

Abstract DBGC is a comprehensive database, integrating various gastric cancer related data resources. In this database, gastric cancer related transcriptomics projects, proteomics projects, mutations, biomarkers and drug sensitive genes from different sources were collected and unified. Besides, follow-up information and clinicopathological information of gastric cancer patients in Shanghai, China, were also integrated through ID-mapping. We believe that this database will greatly facilitate the research work of gastric cancer researchers. Database URL: http://bminfor.tongji.edu.cn/dbgc/index.do Note: This abstract was not presented at the meeting. Citation Format: Yingyan Yu. DBGC: database of gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4855. doi:10.1158/1538-7445.AM2015-4855
Assessment of clinical activity of E7080, a multitargeted kinase inhibitor, in patients with advanced melanoma treated in two phase I trials.
Authors: D. S. Hong, D. S. Boss, H. Glen, J. Mink, M. Ren, C. Andresen, J. P. O'Brien, R. Kurzrock, J. H. M. Schellens, J. J. Nemunaitis, T. R. J. Evans
Journal: Journal of Clinical Oncology (2011)

8527 Background: E7080 is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of E7080, DLTs were hypertension and proteinuria and common toxicities included grade 1-2 fatigue, anorexia, nausea, weight loss and diarrhea. MTD for E7080 once daily (QD) is 25 mg and for twice daily (BID) is 20 mg (i.e.10 mg BID). Methods: From 7/2005 to 10/2008, 82 patients (pts) with advanced solid tumors including 14 with advanced melanoma were enrolled into a phase I study of escalating doses of E7080 QD. From 7/2005 to 8/2009, 77 pts with advanced solid tumors including 29 with advanced melanoma were enrolled into a second phase I study of escalating doses of E7080 BID. 25/29 pts receiving E7080 BID underwent pretreatment biopsy for molecular analysis of tumor vascular and melanoma cell components. Those results are reported separately. Clinical outcomes for melanoma pts treated with E7080 in phase I trials are reported. Results: 35/43 pts received E7080 doses of ≥ 20 mg/day. 5/14 pts receiving E7080 QD had tumor reductions of 20% to 85%, including 2 confirmed PRs. Median progression free survival (PFS) was 7 months. 6 mo PFS was 58%. 7/29 pts receiving E7080 BID, had tumor reductions of 20% to 85% including 3 confirmed PRs. Median PFS for this group was 3.6 months, 6 mo PFS was 25%. For all pts treated in both trials median PFS was 4 mo (95% CI: 3.4-7.1). 6 mo PFS was 35%. Median duration of PR was 15 mo (range: 5-23 mo). Conclusions: E7080 administered to pts with advanced melanoma in two phase I studies achieved PRs and prolonged tumor regression in a subset of patients. Pts receiving QD doses of E7080 ≥20 mg/day appear to have longer PFS compared to pts receiving QD E7080 doses <20 mg/day. A phase II trial is currently ongoing to determine the magnitude of the treatment effect in molecularly defined populations and to identify the molecular features of E7080 responsive melanomas.
Concordance and Prognostic Significance of Minimal Residual Disease Detection in Peripheral Blood and Bone Marrow Samples of Infants with MLL-rearranged Acute Lymphoblastic Leukemia Treated By MLL-Baby Protocol
Authors: Grigory Tsaur, Alexander Popov, Tatyana Riger, Alexander Solodovnikov, Tatyana Nasedkina, Anatoly Kustanovich, Sergey Tsvirenko, Olga Streneva, Egor Shorikov, Leonid Saveliev, Larisa Fechina
Journal: Blood (2014)
The Transient Neutropenia Following G-CSF Administration Is Associated with An Accumulation of Neutrophils in the Pulmonary and Splenic Vasculature.
Authors: Catherine E. Dejesus, Jackson G. Egen, Xavier Alvarez, Mark E. Metzger, Christian A. Combs, Daniela A. Malide, Zu Xi Yu, Robert E. Donahue
Journal: Blood (2009)
Effect of milk thistle <i>(Silybum marianum)</i> on the pharmacokinetics of irinotecan
Authors: P. H. van Erp, M. Zhao, H. Gelderblom, H. J. Guchelaar, A. Sparreboom, S. D. Baker
Journal: Journal of Clinical Oncology (2005)

2096 Background: Milk thistle is one of the most commonly used non-traditional herbal therapies, particularly in Western Europe. The main component of the mixture of flavonolignans in milk thistle, silybin, significantly reduce the activities of CYP3A4 (Ki, ∼32 μM) and UGT1A1 (Ki, ∼1 μM) in human hepatocyte cultures in vitro. Here, we investigated whether milk thistle affects the pharmacokinetics of irinotecan, a substrate for both CYP3A4 and UGT1A1. Methods: Six cancer patients were treated with irinotecan at a dose of 125 mg/m2, given as a 90-min infusion in cycles of once every week. Four days before the second irinotecan administration, patients received standardized capsules from a single batch (GNC, Pittsburgh, PA), each containing 200 mg milk thistle seed extract, three times a day with water, for 14 consecutive days. Pharmacokinetic parameters of irinotecan and its metabolites SN-38, SN-38-glucuronide (SN-38G), and APC were obtained during the first, second, and third weekly administration. Results: During the first irinotecan administration (in the absence of milk thisle), the mean (± SD) irinotecan clearance was 31.2 ± 19.6 L/h. Short term (i.e., 4 days) or more prolonged intake of milk thistle (i.e., 12 days) had no significant effect on irinotecan clearance (cycle 2, 25.4 ± 14.6 L/h; cycle 3, 25.6 ± 13.6 L/h; P = 0.161). The AUC ratio of SN-38 and irinotecan was slightly decreased by milk thistle (cycle 1, 0.0258 vs cycle 2, 0.0223 vs cycle 3, 0.0217; P = 0.047). The relative extent of glucuronidation (AUC ratio of SN-38G and SN-38), as a measure of the potential of milk thistle to modulate the activity of UGT1A1, was similar in the three cycles of treatment (10.8 vs 13.5 vs 13.1; P = 0.636). Likewise, the AUC ratio of the CYP3A4-mediated metabolite APC and irinotecan was unaffected by milk thistle (0.331 vs 0.285 vs 0.337; P = 0.533). The maximum plasma concentrations of the silymarin component silybin at steady state, determined using LC/MS/MS, ranged between 0.0249μM and 0.257μM. Conclusions: This study suggests that silymarin concentrations after intake of recommended doses of milk thistle are too low to significantly affect the function of CYP3A4 and UGT1A1 in vivo, and that milk thistle does not affect the disposition of irinotecan. No significant financial relationships to disclose.
Apple Domain-Specific Anti-Factor XI Antibodies Inhibit Venous-Type Thrombosis with Improved Hemostatic Safety Profiles Compared to Enoxaparin in Primates
Authors: Erik I. Tucker, Ulla M Marzec, Philberta Y Leung, Stephen R Hanson, Norah G Verbout, Sawan Hurst, Owen J.T. McCarty, David Gailani, Andras Gruber
Journal: Blood (2011)
Low incidence of acute mucosal toxicity observed in a series of head and neck cancer patients treated with radiotherapy and immunomodulator AM3
Authors: A. Ramos, A. Hervás, R. Morera, S. Sancho, R. Moris, J. M. Delgado, M. Alvarez-Mon
Journal: Journal of Clinical Oncology (2004)

5565 Background: AM3 is an oral immunomodulator able to increase the inmune responses against microorganisms, and for this reason is used in patients receiving radiotherapy. In humans AM3 decreases the production of proinflammatory cytokines and increases the secretion of inductor cytokines such as granulocyte-monocyte colony stimulator factors. In animal models, AM3 reduces gut mucosa inflammation and the associated bacterial traslocation. We have studied the potential preventive effects of AM3 adjuvant treatment on the radiotherapy induced mucositis in the head and neck (HN) patients (P). Methods: We studied 20 P with histologycally proven squamous HN cancer treated with radiotherapy. Prior surgical procedures other than biopsy were performed in 17 P. Staging: 2 stage II, 5 P III, 13 P IV. Tumor site: oral cavity 4 P, oropharynx 3 P, hipopharynx 3 P, larynx 10 P. RT was administered with standard fractionation of 2Gy/d, five days a week. Total dose ranged from 50 Gy to 66 Gy, mean 64 Gy. AM3 (Inmunoferon®)was given at a dose of 3 g/d orally concurrently with radiotherapy from day 1 of treatment and was sustained 30 days after finalization of radiation therapy. P were routinely assessed at seven-day intervals for acute mucosal toxicity. Interlukin 6 (IL6) serum levels were measured by ELISA. A historic cohort of 20 patients with similar tumor and stage distribution and radiotherapy treatment was analyzed. Results: In AM3 tretaed P severe acute mucosal toxicity was low and quite manageable and even more interesting, resulted in no delays in overall treatment time. Grades of toxicity (RTOG criteria) were as follows: Grade 1: 5 P (25%), Grade 2: 14 P (70%), Grade 3: 1 P (5%). No cases of Grade 4 toxicity nor treatment-related deaths were observed. In the historical control the toxicity G3–4 affected 25% of the patients. We did not observed significative modifications in the serum concentration of IL-6 along the study. Conclusions: These preliminary results show that the adyuvant use of AM3 during radiotherapy for HN cancer shows to reduce the incidence of severe acute (G3–4) mucosal toxicity. No significant financial relationships to disclose.
Soft drink tax could have major effect on health, study finds
Authors: Anne Gulland
Journal: BMJ (2016)

The forthcoming tax on soft drinks could have a major impact on the incidence of dental caries, type 2 diabetes, and obesity, a study in the Lancet has found.1

The tax, due to be introduced in 2018 as part of the government’s childhood obesity strategy, will include two bands: one for soft drinks with more than 5 g of sugar per 100 mL, and a higher one for drinks with more than 8 g/100 mL. The government estimates that the levy will raise £520m (€620m; $646m) in its first year.2

In the study, researchers modelled three scenarios of how industry would respond to the levy: reformulating drinks to cut sugar content; raising prices; and encouraging consumers to switch to lower sugar …
Stereotactic radiation therapy for liver metastases from colorectal cancer: Predictors for outcome.
Authors: I. Fumagalli, S. Dewas, J. Bibault, X. Mirabel, A. Kramar, H. Jarraya, T. Lacornerie, C. Dewas-Vautravers, E. Lartigau
Journal: Journal of Clinical Oncology (2011)

e14013
10. High-Efficiency Transduction of Primary Human CD34+ Hematopoietic Stem/Progenitor Cells by AAV6 Serotype Vectors: Strategies for Overcoming Donor Variation and Implications in Genome Editing
Authors: Zifei Yin, Kanit Bukhai, George Aslanidi, Chen Ling, Mengqun Tan, Mervin Yoder, Philippe Leboulch, Emmanuel Payen, Arun Srivastava
Journal: Molecular Therapy (2016)

We first reported that of the 10 most commonly used AAV serotype vectors, AAV6 is the most efficient in transducing primary human bone marrow-derived CD34+ hematopoietic stem/progenitor cells (HSPCs), both in vitro and in murine xenograft models in vivo (Cytotherapy, 15: 986-998, 2013; PLoS One, 8(3): e58757, 2013). More recently, two independent groups also reported successful transduction of primary human CD34+ cells using the wild-type (WT) AAV6 vectors (Sci. Transl. Med., 7: 307ra156, 2015; Nat. Biotechnol., 33: 1256-1263, 2015), except that multiplicities of infection (MOIs) ranging from 100,000-200,000 vgs/cell were used to achieve ~40-55% transduction efficiency. Furthermore, the transduction efficiency of the WT AAV6 vector varies greatly in HSPCs from different donors, ranging between ~6-87%. Here we report two distinct strategies to further increase the transduction efficiency in HSPCs from donors that are transduced poorly with the WT AAV6 vectors. The first strategy involved modification of the viral capsid proteins where specific surface-exposed tyrosine (Y) and threonine (T) residues were mutagenized to generate a triple-mutant (Y705F+Y731F+T491V) AAV6 vector. The second strategy involved the use of ex vivo transduction at high cell density, which revealed a novel mechanism, which we have termed, 'cross-transduction'. The combined use of these strategies resulted in transduction efficiency exceeding 90% at an MOI of 20,000 vgs/cell in primary human cord blood-derived HSPCs at day 4 (Fig. 1A). scAAV6 vectors were more efficient than ssAAV6 vectors, but at high cell density, there was a modest enhancement in EGFP-positivity even with ssAAV6 vectors. However, 14 days post-transduction, virtually no EGFP-positive cells could be detected (Fig. 1B), suggesting the loss of vector genomes, and hence, the lack of stable integration of vector genomes in HSPCs. Our studies have significant implications in the optimal use of capsid-optimized AAV6 vectors in genome editing in HSPCs. *These authors contributed equally to this work #Co-corresponding authors
399. Evaluation of CD123 Targeting CART Cells in Non-Human Primates
Authors: Linda Dong, Saar Gill, Vijay Bhoj, Olga Shestova, Lori Martin, Daher Ibrahim Aibo, Xiaorui Yao, LeeAnne Talbot, Elizabeth Skuba, Celeste Richardson, Regina Young, Michael C. Milone, Steve Busch, Jennifer Marlowe, Timothy MacLachlan
Journal: Molecular Therapy (2016)

The CAR-T platform has provided an exceptionally potent means to treat cancers that have proven resistant to standard treatments. This potency, however, can work against normal tissue as well. Some clinical trials have identified adverse consequences as a result of CAR-T cell targeting of critical normal tissue. To enable as many targets as possible using the CAR-T cell approach, it is important to understand the potential liabilities of those targets in normal tissues prior to initiating clinical trials. CD123, the IL-3 receptor alpha subunit, is a viable target for treatment of acute myeloid leukemia, as it is expressed highly on primary AML blasts. We have previously shown that, in mice transplanted with human hematopoietic stem cells, CD123 targeting CAR T-cells eradicated these precursors and, in turn, normal hematopoiesis (Gill et al., 2014Gill Saar Tasian Sarah K. Ruella Marco Shestova Olga Li Yong Porter David L. Carroll Martin Danet-Desnoyers Gwenn Scholler John Grupp Stephan A. June Carl H. Kalos Michael Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells.Blood. 2014; 123: 2343-2354Crossref PubMed Scopus (328) Google Scholar). Here, we describe an animal model developed to address the potential effects of targeting CD123 on non-hematopoietic tissue, namely endothelial cells that are found to express significant levels of CD123. An scFv that bound cynomolgus monkey CD123 was identified and a chimeric lentivirus that efficiently transduced monkey PBMCs was developed. Cells were demonstrated to be active in vitro and dosed into monkeys, after which cellular expansion was observed. In vivo safety assessments and histopathology results will be discussed.
SURG-22. ADULT NEUROSURGICAL ONCOLOGY AT A LARGE ACADEMIC QUATERNARY REFERRAL CENTER: IMPACT OF RESIDENCY TRAINING AND VOLUME ON OUTCOME
Authors: Desmond Brown, Benjamin Himes
Journal: Neuro-Oncology (2016)

Neurosurgery is an integral component of brain tumors management. Whether quality can be maintained in practices with large patient volumes incorporating resident education is unknown. We sought to determine the neurosurgical oncology practice patterns and perioperative outcomes in our own very large academic quaternary referral setting and the impact of resident education on patient outcome. Outcomes for adult patients undergoing neurosurgery for cranial tumors between 2009 and 2013 were reviewed. Neurological, regional, and systemic complications and mortality were recorded as well as whether the case was performed primarily by a staff or chief resident service with the assumption that the latter had more autonomy. Data was correlated using additional quality metrics available through the NSQIP database. A total of 5022 adult cranial tumor procedures were performed at our institution in this 5 year period. These included 1092 craniotomies for intraaxial tumors, 573 craniotomies for extraaxial, non-skull base tumors, 608 craniotomies for skull base tumors, 770 transsphenoidal procedures for pituitary or sellar tumors, 467 stereotactic biopsies, and 1511 radiosurgery procedures. Most patients (n=4541; 90.4%) had no complications. Temporary neurological deficits were seen in 279 (5.6%), permanent deficits in 111 (2.2%), and seizures in 27 (0.5%). Regional and medical complications each occurred in 70 patients (1.4%). Perioperative mortality occurred in 19 patients (0.4%). Skull base procedures and stereotactic biopsies accounted for 6 (31.6%) and 7 (36.8%) of the 19 mortalities, respectively. Patient outcomes were independent of resident participation. This is despite the fact that patients treated by chief residents are older, had higher comorbidities and were more likely to undergo emergent procedures. Morbidity and mortality rates are low and compare favorably to other published series. These data suggest that excellent outcomes for adult cranial tumor can be maintained in high volume clinical practices without sacrificing commitment to resident education.