tbuckley/cabot-search huggingface dataset:
465. Transient Production of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Therapy Applications Using Suspension-Adapted HEK 293 Cells in Orbital Shaken Bioreactors
Authors: Daniel R. Blessing, Monique Montavon, Maria de Jesus, Lucia Baldi, Bernard Schneider, Florian M. Wurm, Nicole Déglon
Journal: Molecular Therapy (2015)

Adeno-associated virus (AAV) is one of the most popular vectors for gene therapy applications. AAV mediated gene therapy approaches offer the advantages of safety, a broad tissue tropism and limited host immune response. Today one commonly used AAV production platform for pre-clinical and clinical use is based on transient transfection of adherent HEK 293 cells grown in serum containing media. This production method is difficult to scale-up and labor intensive, therefore cost-effective and scalable protocols are needed. The use of orbital shaking technology allows the cultivation of HEK 293 cells up to a 1,000 Liter scale in disposable vessels. Here we describe the production of recombinant AAV serotypes 6 and 9 using polyethyleneimine (PEI) based transfection of suspension adapted HEK 293 cells. A two-plasmid system was used to produce the rAAV serotypes in three different suspension-adapted HEK 293 cell lines and one adherent HEK 293 standard. Suspension cells were cultivated in serum-free medium in disposable, orbital shaken bioreactors (OSR) of different scales from 5 ml to 500 ml. Optimization of transfection parameters like cell density at the time of transfection, the ratio of helper to donor plasmid and total plasmid to PEI was conducted for each individual cell line. Lysates and supernatants were processed separately using gradient centrifugation and affinity chromatography. Purified virus stocks were then analyzed and titrated using methods to determine total viral particles, viral genomes and infectious titers. Preliminary results indicate that rAAV particles produced with suspension cells yield infectious titers equal or higher than particles produced by standard methods based on adherent cells. Further work is ongoing to analyze and implement this OSR platform. The presented process offers a novel method to produce rAAV for preclinical and clinical trials compliant to GMP, single-use and scalable.
High glucose promotes mouse embryonic stem cells growth through PGE2 and PPAR-δ signaling pathways
Authors: Yun Hee Kim, Sang Hun Lee, Han Na Suh, Mi Ok Kim, Yu Jin Lee, Jung Min Ryu, Seung Pil Yun, Jae Hong Park, Ho Jae Han
Journal: Clinical Cancer Research (2007)

C8   Peroxisome proliferator-activated receptor is a nuclear receptor that has been implicated in blastocyst implantation, lipid metabolism, cell cycle, and pathogenesis of diabetes. However, the signal cascades underlying this effect are largely unknown in embryonic stem (ES) cells. This study examined whether or not there is an association between the reactive oxygen species-mediated prostaglandin E 2  (PGE 2 )/peroxisome proliferator-activated receptor (PPAR) δ and the growth response to high glucose levels in mouse ES cells. A high glucose (25 mM) significantly increased the level of [ 3 H]thymidine incorporation, BrdU incorporation, and the number of cells. Moreover, 25 mM glucose increased the intercellular reactive oxygen species (ROS), phosphorylation of the cytosolic phospholipase A 2  (cPLA 2 ), and the release of [ 3 H]labeled arachidonic acid (AA). In addition, 25 mM glucose also increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of PGE 2 . Subsequently, the increase in PGE 2  production stimulated PPARδ expression directly or through Akt phosphorylation indirectly through the EP receptors. The PPARδ antagonist inhibited the 25 mM glucose-induced DNA synthesis. Moreover, transfection with a pool of PPARδ specific siRNA inhibited the 25 mM glucose-induced DNA synthesis and G1/S phase progression. Twenty five mM glucose also increased the level of the cell cycle regulatory proteins [cyclin E/cyclin-dependent kinase (CDK) 2, cyclin D1/CDK 4] and decreased p21  WAF1/Cip1  and p27 Kip1 , which were blocked by the inhibition of the cPLA 2 , COX-2 or PPARδ pathways. In conclusion, high glucose in part promotes mouse ES cell growth through the cPLA 2 -mediated PGE 2  synthesis and PPARδ pathways.   KEY WORDS: High glucose (HG), Embryonic stem (ES) cells, Peroxisome proliferators-activated receptor (PPAR) δ, prostaglandin E 2  (PGE 2 )
10 Years Follow-up of the GELA LNH98.5 Study, First Randomized Study Comparing R-CHOP to CHOP Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma.
Authors: Bertrand Coiffier, Christian Gisselbrecht, Andre Bosly, Raoul Herbrecht, Reda Bouabdallah, Pierre Morel, Eric Van Den Neste, Dominique Bordessoule, Corinne Haioun, Herve Tilly, Gilles Salles
Journal: Blood (2009)
Relation of clinical variables to dissociative phenomena in eating disorders
Authors: M A Demitrack, F W Putnam, T D Brewerton, H A Brandt, P W Gold
Journal: American Journal of Psychiatry (1990)

In this study 30 female patients with eating disorders were compared with 30 age-matched normal female subjects. The patients demonstrated significantly higher levels of dissociative psychopathology than the comparison subjects. Furthermore, the presence of severe dissociative experience appeared to be specifically related to a propensity for self-mutilation and suicidal behavior. These findings are discussed in light of recent data which suggest that neurochemical systems shown to be abnormal in patients with eating disorders may be key pathophysiologic substrates for dissociative experience.
Completeness and effectiveness of reporting on three drugs: Lessons learned from RADAR, a novel pharmacosurveillance and pharmacovigilance program
Authors: R. Chacko, S. A. Klinge, S. Luminari, M. Fotis, J. McKoy, S. M. Belknap, D. W. Raisch, G. Schumock, M. S. Tallman, C. L. Bennett
Journal: Journal of Clinical Oncology (2004)

3201 Background: One objective of the Research on Adverse Drug reactions And Reports (RADAR) project is to analyze the comprehensiveness and clinical characteristics of ADRs submitted to FDA reports and the medical literature. Methods: Herein, we review our analysis of three drug-associated ADRS: Gemtuzumab ozogamicin (GO)-associated veno-occlusive disease (VOD), gemcitabine- associated interstitial pneumonitis and thalidomide-associated DVT/PE. RADAR analyzed the completeness of clinical trial (n=163) versus non-clinical trial (n=318) reports. Data was compared via Fisher's exact test, and the resulting p values were combined across drugs via Edgington's (1972) procedure. Results: Overall, clinical trial reports more often reported drug administration date, onset date and the number of days until ADR onset (p<0.0002 for all). Additionally, GO and Thalidomide clinical trial reports were more likely to report diagnostic testing (p<0.003) and GO was more likely to have drug dose and drug schedule (p< 0.001). In reviewing the clinical understanding of each ADR, RADAR highlighted the increased risk of prescribing HSCT with GO or various intensive concomitant chemotherapies with GO, thalidomide and gemcitabine. RADAR also found that three different monitoring strategies (GO-prospective study, Gemcitabine-volunatry reporting and Thalidomide-safety registry (STEPS)) were deficient, indicating that more diligent reporting is needed. Conclusions: RADAR advocates the creation of a consortium of adverse event monitoring programs at major clinical research centers to act as an early detection system for adverse drug reactions. No significant financial relationships to disclose.
Cytogenetic responses to the hypomethylating agent, decitabine (DAC), in a phase III trial of DAC vs supportive care (SC) in patients (pts) with myelodysplastic syndromes (MDS)
Authors: J. Issa, H. M. Kantarjian, H. I. Saba
Journal: Journal of Clinical Oncology (2006)

6501 Background: Clonal cytogenetic abnormalities are detected in 40%-70% of cases of de novo MDS and 95% of cases of therapy-related MDS, and the incidence increases with poor risk. DAC is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. In this analysis, we asked whether the hypomethylating agent DAC leads to cytogenetic response in MDS. Methods: We report cytogenetic response data from a Phase III randomized, open-label trial of DAC vs SC in 170 MDS pts. Eligibility requirements included confirmed MDS (de novo or secondary) fitting any of the recognized French-American-British classifications and an International Prognostic Scoring System (IPSS) score of 0.5 or more as determined by complete blood count, cytogenetics, and bone marrow assessment. Cytogenetics was assessed as a secondary endpoint, whereas primary endpoints were response rate (CR+PR) and time to AML or death. For pts with clonal abnormalities at baseline, follow-up cytogenetic evaluations at study end were available for 26 pts in the DAC arm and 21 pts in the SC alone arm. Results: As previously reported, overall response rate according to International Working Group MDS criteria was 17% (15/89) for DAC vs 0% for SC (p&lt;0.001). Responses occurred in all IPSS groups and were also seen in pts with 5q and 7 deletions. Response rate was 13% (2/16) in pts with 5q deletions and 21% (4/19) in pts with 7 deletions. In pts without 5q or 7 deletions, response rates were 16% (11/67) and 14% (9/64), respectively. Complete cytogenetic responses were observed in 35% (9/26) of DAC pts vs 10% (2/21) of SC pts (p=0.08, Fisher’s exact). Also, 1 pt receiving DAC had a minor cytogenetic response. 10/10 DAC pts with cytogenetic response had clinical benefit (6 CR, 2 PR, 1 hematologic improvement, and 1 with normalization of marrow blast count). The primary toxicity was myelosuppression. Conclusion: DAC induces a substantial rate of cytogenetic responses in pts with MDS, suggesting that the clinical improvements induced by this agent are related to elimination of the neoplastic clone rather than to pure differentiation effects. [Table: see text]
Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab: Clinical Activity Including Survival in Patients with Recurrent/Refractory Follicular or ‘Aggressive' Lymphoma.
Authors: Nam H. Dang, Mitchell R Smith, Fritz Offner, Gregor Verhoef, Peter Johnson, Ama Z S Rohatiner, Jonathan L. Kaufman, Eva Gine, Bertrand Coiffier, Myron S Czuczman, James Foran, Simon Durrant, Steven Hua, Erik R. Vandendries, Luis Fayad
Journal: Blood (2009)
Gender differences in the onset of symptoms of cancer-related anemia
Authors: J. Levar, W. Jordan, S. Laird, L. Mandell, G. Friess, M. Ross, R. Page
Journal: Journal of Clinical Oncology (2004)

8100 Background: Baseline differences in red blood cell mass between men and women may need to be considered in the management of cancer-related anemia with recombinant human erythropoetin (rHuEPO) for QoL benefit. Methods: Valid information on patient fatigue was collected from 197 patients with solid tumors via the Functional Assessment of Cancer Therapy - Anemia (FACT - An) subscale questionnaire. Additional patient information including diagnosis, age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, current therapy, and hemoglobin level was recorded and considered for a possible role in patient fatigue. Results: Hemoglobin concentration was positively correlated with FACT-An subscale score (p < .001), as were improvements in ECOG performance status by regression analysis (p < .001). Patients receiving chemotherapy experienced greater fatigue than those who were not by independent t-test (p < .01). Regression analysis revealed that patient age did not have a statistically significant impact on FACT-An subscale score (p = .07). Controlling for the potentially confounding effects of ECOG performance status and current therapy, analysis of covariance found that male patients experienced a significantly greater level of fatigue than did females when considering respondents of all hemoglobin values (p < .05). However, this difference was only significant among patients in the 10.0 –13.0 g/dL hemoglobin range (p < .01) with diminishing disparity at greater hemoglobin levels. Conclusions: Men begin to experience the symptoms of cancer-related anemia at relatively greater hemoglobin values than do females, and at equivalent hemoglobin concentrations, men report greater fatigue. These data suggest that male patients require earlier intervention and the maintenance of hemoglobin concentration at greater target levels when using rHuEPO for QoL benefit. No significant financial relationships to disclose.
The Love/Avon Army of Women: A “just in time” resource to encourage research in women
Authors: S. M. Love, D. Mills, E. Eraklis, M. Hurlbert
Journal: Journal of Clinical Oncology (2009)

1535 Background: One of the barriers to finding the cause of breast cancer is the difficulty basic scientists have in involving healthy women and obtaining human tissues, fluids, and information processed according to their needs. The Dr. Susan Love Research Foundation has collaborated with basic scientists successfully recruiting community women for studies. These efforts led to the Love/Avon Army of Women (AOW), a new “just in time” resource seeking to partner women with scientists to find the cause and prevention of breast cancer. Methods: The AOW is a pool of volunteers who have registered online ( www.armyofwomen.org ) that they are willing to participate in research. Peer-reviewed, funded projects submitted by researchers are reviewed by the AOW Scientific Advisory Committee for eligibility. An eBlast is sent to all AOW volunteers describing the study, and eligible women RSVP to the AOW for a secondary screen. The list is then sent to the researcher. If needed, referrals are made to a regional AOW Center for specimen collection, processing, and shipment. All scientists participate in a webcast with the eligible volunteers to explain the research before the study and describe the overall results at the end, ensuring a partnership between the women and the investigators. Results: AOW recruitment was initiated October 1, 2008, by Dr. Love on national media with the goal of creating a resource of 1,000,000 women available for researchers. To date over 260,000 women have joined. All ethnicities, ages (18–89), and states are represented. The first eBlast was sent out in mid-October for the Sister Study to accrue the last 5,000 women needed from diverse backgrounds. In 48 hours, 1,600 women had responded and qualified, and in 2 months, 2,500 had signed up with a 90% enrollment rate. The second study required women who were breastfeeding and scheduled for a breast biopsy. In one week, 30 eligible women were identified. Conclusions: The Love/Avon Army of Women is a just in time resource for breast cancer scientists to obtain exactly the specimens: breast or adipose tissue, ductal fluid, urine, saliva, blood, or information processed exactly as needed. This new partnership between women and scientists promises to revolutionize research and accelerate efforts to find the cause and prevention of breast cancer. No significant financial relationships to disclose.
Circadian dysrhythm and advanced prostate cancer.
Authors: Lorelei A. Mucci, Sarah Markt, Lara Sigurdardottir, Steven W. Lockley, Katja Fall, Meir J. Stampfer, Vilmundur Gudnason, Peter Kraft, Jennifer R Rider, Charles A Czeisler, Unnur Anna Valdimarsdottir
Journal: Journal of Clinical Oncology (2014)

199 Background: The circadian rhythm regulates diverse biologic pathways including tumor oncogenes, metabolism, and cell proliferation. Dysregulation of the circadian rhythm arises from faulty input signals such as exposure to light at night, variability in core circadian rhythm genes, and variation in outputs that regulate circadian behavior including melatonin. There is compelling biologic rationale, but little human data, on circadian dysrhythm and advanced prostate cancer. Methods: We undertook an integrative molecular epidemiology study of circadian dysrhythm and advanced prostate cancer among men in the Icelandic AGES-Reykjavik cohort and the U.S. Health Professionals Follow-up Study, which allowed integration of questionnaire data, biorepositories, and long-term follow-up. We characterized circadian dysrhythm using complimentary approaches: information on sleep problems from questionnaires, prediagnostic melatonin (6-sulfatoxymelatonin) measured on first morning void urine samples, and genetic variation across twelve circadian clock genes. We used multivariable regression models to estimate relative risks (RR) and 95% confidence intervals (CI) of associations with advanced prostate cancer, adjusted for potential confounders. Results: Twenty percent of men reported sleep problems. Men who had trouble falling asleep (RR = 2.1; 95% CI 0.7-6.2) and staying asleep (RR=3.2, 95% CI 1.1-9.7) had an increased risk of developing advanced prostate cancer. Men with sleep problems had significantly lower melatonin levels compared to those without. Low melatonin levels were associated with a statistically significant 4-fold higher risk of advanced prostate cancer compared to those with high levels (95% CI: 1.25-10.0). Variant alleles in two SNPs in cryptochrome (CRY1), involved in generating and maintaining circadian rhythms, were significantly associated with risk of advanced prostate cancer in both cohorts, with a gene-level p-value&lt;0.01. Conclusions: Our results suggest there are multiple nodes in the circadian rhythm that are associated with an increased risk of advanced prostate cancer. As such, there is the potential for complimentary strategies to target circadian disruption and reduce the risk of advanced prostate cancer.
An analysis quantifies prostate brachytherapy swelling using peripheral seeds as fiducial reference points
Authors: K. J. Minehan, D. Groshek, K. McNamara, E. Mitchell, M. Emme, M. Price, B. Davis
Journal: Journal of Clinical Oncology (2007)

15639 Background: Permanent prostate brachytherapy (PPB) assesses implant quality but may suffer significant variability due to: 1) Prostate edema may occur during the procedure which usually subsides within several months, and 2) interobserver variability of CT- derived prostate volumes. An analysis is described, which uses the seeds as prostate fiducials to produce an implant reference volume (IRV). The ratio of the IRV volumes at day 0 and day 33 provides a unique way to quantify prostate edema; thus reducing this factor as a source of variability. Methods: Thirteen low risk prostate cancer patients, (Stage ≤ T2, PSA&lt;13.9, Gleason Score ≤7) were implanted with 125 Iodine seeds (77% stranded; prescription dose of 145 Gy). PPB was completed for each patient on day 0 and 33 ±3 days following the implant. The IRV was defined as the volume obtained by contouring the outer most peripheral seeds, circumferentially, on each axial image, resulting in a 3D volume. Contouring was performed by three separate investigators (KJM, DCG, EKM), who were blinded with respect to patient identification. The IRV's were compared both by investigator and by time of PPB (day 0 vs. day 33). The radiation dose encompassing 90% (D90) of the IRV and Prostate (PST) was calculated and compared . Results: The IRVs contoured were reproducible between the investigators with a maximum mean difference of .56 (SD .33) cc. There was no statistical difference between any of the investigators contoured volume (minimum Spearman correlation was 0.978). The average IRV was significantly larger on day 0 (Avg. 52.7;SD 19.7 cc) compared to day 33 (Avg. 44.6; SD 19.1 cc) (p&lt;0.001). The day 0 IRV was an average of 1.18 times larger than the Day 33 PRV. There was no difference between either the day 0 D90 PST (Avg.149.1; SD18.7 cGy) vs the day 0 D90 IRV (Avg.149.8, SD 27.5 cGy) (p=.442) nor between the day 33 D90 PST (Avg.163.7; SD22.7 cGy) vs the day 33 D90 IRV (Avg.166.6, SD 30.3 cGy) (p=.257). Both the D90 IRV and D90 PST were significantly different at day 0 vs 33 (p=.0003, p=&lt;.0001 respectively). Conclusions: The IRV analysis demonstrates no significant interobserver variability, provides accurate quantification of prostate swelling after PPB, and is an accurate objective surrogate analysis for PSI quality. No significant financial relationships to disclose.
Abstract 16517: Intracoronary Compared with Intravenous Bolus Abciximab Application During Primary Percutaneous Coronary Intervention - Cardiac Magnetic Resonance Imaging Substudy of the Aida Stemi Trial
Authors: Ingo Eitel, Jochen Woehrle, Henning Suenkel, Josefine Meissner, Bernward Lauer, Matthias Pauschinger, Petra Neuhaus, Oana Brosteanu, Sebastian Kerber, Matthias Gutberlet, Ralf Birkemeyer, Christoph Axthelm, Steffen Desch, Gerhard Schuler, Holger Thiele
Journal: Circulation (2012)
Molecular subtyping using MammaPrint and BluePrint as an outcome predictor in U.S. breast cancer (BC) patients.
Authors: Katharine Yao, Mary Turk, Karen Kaul, JoEllen Weaver, Femke De Snoo, Lisette Stork-Sloots, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2012)

9 Background: Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy (Glück SABCS2011). The aim of this study was to evaluate the prognostic value of Molecular Subtyping using MammaPrint and BluePrint in women with early stage BC treated at U.S. institutions following National Comprehensive Cancer Network (NCCN) standard guidelines. Methods: Frozen tumor samples from 180 BC patients (TI-III, N0-Ib) median age 57 years at diagnosis (range 28-89) were suitable for hybridization on full genome array. MammaPrint and BluePrint Molecular Subtypes were determined and survival for Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint High Risk), HER2-type and Basal-type patients was assessed. Patients were treated either with breast conserving therapy or mastectomy with axillary lymph node dissection between 1992 and 2005. The median follow-up is 12.7 years. 71% was ER positive and 20% Her2 positive by IHC/FISH. 58% received adjuvant endocrine therapy (ET) (excluding 13 patients unknown treatment), 64% received adjuvant chemotherapy (CT) (excluding 12 patients unknown treatment) and 33% received both. Results: 61 (34%) Patients with MammaPrint Low Risk/Luminal-type (Luminal A) showed 5-year DFS of 97% (34% received CT and 69% ET) and 50 (28%) patients with MammaPrint High Risk/Luminal-type (Luminal B) had a 5-year DFS of 98% (60% received CT and 68% ET). Patients with BluePrint Basal-type tumors (46 (26%)) had a 5-year DFS of 80% (78% received CT); HER2-type (23 (13%)) had a 5-year DFS of 78% (87% received CT without HER2 targeted therapy). Conclusions: In this retrospective study evaluating 180 US patients with early BC treated according to standard guidelines we showed how combining BluePrint with MammaPrint can detect molecularly defined subgroups of patients who are at high risk of recurrence (HER2 and Basal-type). Furthermore, we confirmed that molecularly defined Luminal type disease is associated with excellent disease-free survival. MammaPrint and BluePrint molecular and prognostic stratification should be prospectively evaluated for therapeutic selection.