tbuckley/cabot-search huggingface dataset:
Comparison of acute toxicity in patients treated with a 4-field box or IMRT to deliver elective pelvic nodal irradiation for localized high-risk prostate cancer.
Authors: Suneil Jain, Patrick Cheung, D. Andrew Loblaw, Gerard Morton, Cyril Danjoux, Ewa Szumacher, William Chu, Hans T. Chung, Danny Vesprini, Arjun Sahgal, Liying Zhang, Andrea Deabreu
Journal: Journal of Clinical Oncology (2012)

69 Background: To deliver elective pelvic nodal irradiation (EPNI), a 4-field box (4FB) has been a common technique. More recently, there are increasing reports of using IMRT to deliver EPNI. Even though studies show a clear dosimetric benefit to bowel and bladder, there is a lack of good data demonstrating decreased toxicity with the use of IMRT in this setting. Methods: From 2004-2010, 230 patients with localized high risk prostate cancer were enrolled into 3 sequential prospective phase I/II trials of delivering EPNI (45 Gy) along with a concomitant hypofractionated IMRT boost to the prostate (67.5 Gy total) in 25 fractions over 5 weeks time. All patients were to receive 3 years of adjuvant androgen deprivation. During the accrual period, the method used to deliver the EPNI portion of the treatment changed as new literature emerged about target volumes for EPNI. The 3 methods used to deliver EPNI in this large cohort were 1) 4FB, 2) IMRT with 2cm CTV margins around the pelvic vessels as suggested by Shih et al (IMRT-Shih), and 3) IMRT with nodal volumes as suggested by RTOG (IMRT-RTOG). Common Terminology Criteria for Adverse Events v3.0 was used to assess acute toxicity prospectively during treatment and then at 3 months. Results: For EPNI, 94 patients were treated with a 4FB, 53 were treated with IMRT-Shih, and 83 were treated with IMRT-RTOG. There were no acute grade 3 GI toxicities. Patients in the 4FB group had higher rates of acute grade ≥ 2 proctitis compared to the IMRT-Shih and IMRT-RTOG groups (16.0% vs 2.0% vs 2.4%, p=0.0009). The 4FB group also had higher rates of grade ≥ 2 flatulence compared to the 2 other IMRT groups (17.0% vs 7.6% vs 0%, p&lt;0.0001). With regards to acute GU toxicities, patients in the 4FB group had higher rates of grade ≥ 3 urinary frequency compared to the 2 other IMRT groups (5.3% vs 0% vs 0%, p=0.027). Conclusions: In this non-randomized comparison, IMRT resulted in statistically significant decreases in acute proctitis, flatulence, and urinary frequency when compared to a 4FB technique to deliver EPNI in localized high risk prostate cancer. Analysis for possible confounding factors will be performed.
314. Systemic Vascular Transduction Following Intravenous Injection of Capsid Mutant Adeno-Associated Virus
Authors: Daniel M. Lipinski, Chris A. Reid, Sanford L. Boye, James J. Peterson, Xiaoping Qi, Michael E. Boulton, William W. Hauswirth
Journal: Molecular Therapy (2015)

The ability to effectively deliver genetic material to vascular endothelial cells remains one of the greatest unmet challenges facing the development of gene therapies to prevent diseases with underlying vascular aetiology, such as diabetes, atherosclerosis and age-related macular degeneration. Herein, we assess the effectiveness of a rAAV2-based capsid mutant vector (Y272F, Y444F, Y500F, Y730F, T491V; termed, QuadYF+TV) with strong endothelial cell tropism at transducing the vasculature following systemic intravenous administration. QuadYF+TV expressing an EGFP or luciferase reporter gene from a vascular endothelial cell specific (VECadherin) promoter was injected intravenously at high titre (1012gp per animal) in wild type (C57Bl/6j and Balb/c) mice via the retro-orbital venous sinus; control animals received intravenous injection of either unmodified AAV2 or PBS. Systemic transgene expression was assessed by in vivo bioluminescence imaging (luciferase) with cellular tropism confirmed by post-mortem histopathology (EGFP); vector genome distribution was quantified by qPCR assay of tissue samples harvested from all organs and correlated to the observed expression levels. Intravenous administration of QuadYF+TV.EGFP vector resulted in widespread transgene expression throughout the vasculature of most major organ systems, including the lungs, liver, pancreas and eyes. In vivo bioluminescence imaging of QuadYF+TV.Luciferase injected mice (n=9) revealed diffuse signal throughout the body and substantially reduced liver expression compared to unmodified AAV2 injected mice. Intravenous administration of QuadYF+TV vector resulted in effective transduction of blood vessels in several organ systems and substantially reduced liver expression compared to unmodified AAV2. The ability to target the vascular endothelium efficiently represents a significant advance towards the development of AAV-mediated gene therapies for the treatment of diseases stemming from underlying vascular dysfunction.
Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody
Authors: George A. Dominguez, Thomas Condamine, Sridevi Mony, Ayumi Hashimoto, Fang Wang, Qin Liu, Andres Forero, Johanna Bendell, Robert Witt, Neil Hockstein, Prasanna Kumar, Dmitry I. Gabrilovich
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs. Experimental Design: The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated. Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies. Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942–50. ©2016 AACR.
Aberrant Expression of LMO2, TAL1 (SCL) and T- RALDH2 in the T-Cell Clone of a Patient with T-ALL like Syndrome after Gene Therapy for X1-SCID.
Authors: Gerlinde Layh-Schmitt, Antonia Rosenstiel, Chuck Klanke, Kathleen Anderson, Salim Hacein-Bey-Abina, Alan Fischer, Marina Cavazzano-Calvo, Christof von Kalle
Journal: Blood (2004)
59. APPsα Gene Therapy for Alzheimer's Disease
Authors: Romain Fol, Susann Ludewig, Tobias Abel, Sascha W. Weyer, Jan-Peter Roederer, Florian Brod, Mickael Audrain, Alexis-Pierre Bemelmans, Christian J. Buccholz, Martin Korte, Ulrike C. Müller, Nathalie Cartier-Lacave
Journal: Molecular Therapy (2016)

Alzheimer's disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions asociéted with β-amyloid accumulation and neurofibrillary tangles of phosphorylated Tau protein. Increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. We used an AAV vector to directly overexpress APPsa in the brain and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1ΔE9 AD mouse model. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial memory. A significant reduction of both toxic soluble β42 and plaque load was evidenced. APPsα induced the recruitment of microglia with ramified morphology towards plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. APPsα overexpression in the brain using an AAV vector improves synaptic and cognitive deficits, despite established pathology and may be of therapeutic relevance for AD.
Abstract 1767: Anti-proliferative and anti-invasive action of omega-3 polyunsaturated fatty acids in stomach cancer cells
Authors: Soyeon Shin, Soyeon Jeong, Soyeon Kim, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim
Journal: Cancer Research (2015)

Abstract The American Cancer Society has been reported that about 22,220 cases of stomach cancer will be diagnosed and about 10,990 patients will die from this type of cancer in 2014. Omega-3 polyunsaturated fatty acids (ω3-PUFA), including docosahexaenoic acid (DHA) have been suggested to have anti-cancer effects by epidemiological and clinical studies. However, their underlying anti-cancer mechanisms are still unclear in stomach cancer. This study was designed to examine the impact of ω3-PUFA on stomach cancer and the molecular mechanism of their action. DHA reduced cells viability in a dose- and time-dependent manner in human stomach cancer cells including AGS cells. The DHA-induced cells death was in part due to apoptosis, since the cells exhibited increases of apoptotic markers including cleaved PARP and TUNEL-positive cells. DHA also led to autophagic vesicle formation an increase levels of lipidated form LC3B and stimulated the autophagic flux, indicating the involvement of both apoptosis and autophagy in the cytotoxic effect of stomach cancer cells by ω3-PUFA. Moreover, AGS stable cell expressing the ω3-desaturase (fat-1) gene (AGS-fsc) or control vector stable cell (AGS-csc) were eatablished, and the effect of endogenous high level of ω3-PUFA was investigated in AGS cells. The cell proliferation, invasion and colony-formation were inhibited in AGS-fsc compared to AGS-csc. Taken together, these results indicate that ω3-PUFA induce anti-cancer action is related to anti-proliferation and anti-invasive action in stomach cancer cells. Thus, utilization of ω3-PUFA may represent a promising therapeutic approach for chemoprevention and treatment of human stomach cancer. [This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2014R1A1A2008915) and by the Korea government(MSIP) (No. 2007-0054932)] Citation Format: Soyeon Shin, Soyeon Jeong, Soyeon Kim, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Anti-proliferative and anti-invasive action of omega-3 polyunsaturated fatty acids in stomach cancer cells. [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 1767. doi:10.1158/1538-7445.AM2015-1767
Plasmablastic Lymphoma: 28 Patient Single Institution Experience
Authors: Krina Patel, Lei Feng, Yasuhiro Oki, Muzaffar Qazilbash, Tariq Muzzafar, Donna M. Weber, Nathan Fowler, Uday R Popat, Sheeba K. Thomas, Michelle A. Fanale, Yago Nieto, Nina Shah, Qaiser Bashir, Fredrick B. Hagemeister, Robert Z. Orlowski, Jatin J. Shah
Journal: Blood (2013)
Increased Levels of Reactive Oxygen Species and Exhaustion of the Quiescent CD34+ Cells May Operate in Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yuan Kong, Yue Hu, Yang Song, Yu-Tong Wang, Zheng-Fan Jiang, Hong-Kui Deng, Xiao Jun Huang
Journal: Blood (2015)
Abstract 4709: Compartmental flexibility in mammalian folate metabolism
Authors: Gregory S. Ducker, Li Chen, Xin Teng, Joshua D. Rabinowitz
Journal: Cancer Research (2015)

Abstract Background: Folate metabolism occurs in parallel cytosolic and mitochondrial pathways. Increased mitochondrial, but not cytosolic, folate dependent serine catabolism is among the most consistent metabolic alterations in human tumors. This study employs genetics coupled with quantitative metabolic analysis to determine the respective requirements for compartmentalized folate metabolism in proliferating human cells. Methods: Using CRISPR-Cas9 technology, we created a library of deletion mutant cell lines for enzymes in folate metabolism. Cellular metabolites from these cells were quantified by liquid chromatography mass spectrometry (LC-MS). Compartmental specific folate metabolic fluxes were assayed by labeling experiments using isotopic tracers of serine, glycine and formate. Results: We show that in HEK 293T cells, as well as in many but not all human cancer cell lines, folate dependent serine catabolism occurs predominantly in the mitochondria. In mutant cell lines deficient for mitochondrial folate genes, the reversal of the direction of cytosolic one-carbon flux enables cell growth, albeit at a reduced rate and with metabolic hallmarks of 10-formyltetrahydrofolate deficiency. Addition of exogenous formate rescued the 10-formyltetrahydrofolate deficiency in all mutants, but the growth defect in only a subset. The growth defect persisted in cell lines mutant for enzymes required for the generation of mitochondrial one-carbon units and folate dependent generation of NAD(P)H but not for the production of formate. Conclusions: This study finds that folate metabolism is flexible with respect to compartmentalization. Cytosolic folate metabolism can provide sufficient one-carbon flux to fuel cell growth even in the complete absence of mitochondrial activity. High expression of mitochondrial folate genes in cancer may function to meet biosynthetic requirements under the stressful conditions of the tumor or to provide necessary compartmentalized one-carbon units and/or reducing equivalents. Citation Format: Gregory S. Ducker, Li Chen, Xin Teng, Joshua D. Rabinowitz. Compartmental flexibility in mammalian folate metabolism. [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 4709. doi:10.1158/1538-7445.AM2015-4709
Abstract 4913: Highly complex oligonucleotide libraries for use in high-resolution RNA and RNA/DNA fluorescence in situ hybridization in various sample types
Authors: Robert A. Ach, Mistuni Ghosh, Peter Tsang, Alicia Scheffer-Wong, Laurakay Bruhn, Alice Yamada
Journal: Cancer Research (2015)

Abstract Fluorescence in situ Hybridization (FISH) is a powerful technique for determining the localization specific nucleic acid sequences within individual cells. Previously, the use of FISH has often been dependent upon access to cloned template DNA for the generation of probes, which can be difficult if clones for specific regions are unavailable, or if the genomic region of interest contains repetitive and/or other problematic sequences. We have developed the ability to chemically synthesize DNA in massively parallel reactions, which we have used to produce libraries of oligonucleotides up to 200 bases in length that can be utilized for the generation of FISH probes. The sequences of the oligonucleotides in these libraries are selected in silico using empirically determined criteria so as to avoid repetitive elements or regions homologous to other non-targeted loci. We have found that these oligonucleotide library-derived FISH probes can detect human genomic regions as small as 1.8 kb and as large as whole chromosomes in both metaphase and interphase cells, using the same simple assay protocol. Because of the inherent flexibility in our probe design methods, we can readily visualize regions rich in repeats and/or GC content. We have also used these oligonucleotide library-derived FISH probes to detect the localization of a variety of both coding and non-coding RNAs in fixed tissue culture cells and formalin-fixed paraffin-embedded tissue sections, using both conventional fluorescence and structured illumination microscopy. Simultaneous hybridization of FISH probes labeled with different fluorophores enables visualization of multiple sequences at once. Using probes designed specifically to transcribed vs. non-transcribed regions has enabled the simultaneously detect DNA and RNA from the same locus, or from two different loci, in the same FISH assay. The ability to generate high performance FISH probes using chemically synthesized oligo libraries that can simultaneously detect DNA and RNA yields a valuable tool for studies of how localization of specific nucleic acids impacts biological function. Citation Format: Robert A. Ach, Mistuni Ghosh, Peter Tsang, Alicia Scheffer-Wong, Laurakay Bruhn, Alice Yamada. Highly complex oligonucleotide libraries for use in high-resolution RNA and RNA/DNA fluorescence in situ hybridization in various sample types. [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 4913. doi:10.1158/1538-7445.AM2015-4913
Abstract 888: Reproductive and hormonal factors and mortality risk among women with colorectal cancer in the NIH-AARP Diet and Health Study
Authors: Hannah Arem, Yikyung Park, Ashley Felix, Alice Zervoudakis, Louise A. Brinton, Charles E. Matthews, Marc J. Gunter
Journal: Cancer Research (2015)

Abstract Introduction Women in the US have lower rates of colorectal cancer than men, which has prompted research into the role of estrogen in carcinogenesis. While use of menopausal hormone therapy (MHT) and other hormonally-related factors have been associated with lower risk of colorectal cancer (CRC), associations between these factors and colorectal cancer survival are not well defined. Methods The NIH-AARP cohort includes 566,398 AARP members (aged 50-71 years) who resided in one of six US states or two metropolitan areas and completed a mailed baseline questionnaire in 1995-1996. Among 2,053 women with incident colorectal cancer in the NIH-AARP Diet and Health Study, we examined associations of age at menarche, age at menopause, age at first birth, parity, oral contraceptive use, and menopausal hormone therapy use with overall and disease-specific mortality. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and disease-specific mortality, adjusting for tumor stage and grade, treatment, years since diagnosis, body mass index, marital status, smoking status, diabetes, and physical activity. Results There were 759 deaths (332 due to CRC) over a median 7.7 years of follow-up. We observed a suggestive, but not statistically significant, lower risk of all-cause mortality among women who were 13 years or older at menarche compared to those 12 or younger (HR = 0.89, 95% CI 0.77-1.03), but no associations for age at menopause, age at first live birth, parity, or oral contraceptive use. Compared to never MHT use former MHT use was not associated with mortality risk, but we found an inverse association among current users at study entry for both all-cause mortality (HR = 0.80, 95% CI 0.67-0.94) and colorectal cancer-specific mortality (HR = 0.72, 95% CI 0.56-0.93). These associations were stronger among those who reported fewer than five years of MHT use at baseline than among those with a longer duration of use. Conclusion We found evidence of an inverse association between MHT use at study entry and all-cause and colorectal cancer-specific mortality risk. Future studies should focus on how varying usage patterns, including types of preparation used, affect tumor progression and colorectal cancer survival. Citation Format: Hannah Arem, Yikyung Park, Ashley Felix, Alice Zervoudakis, Louise A. Brinton, Charles E. Matthews, Marc J. Gunter. Reproductive and hormonal factors and mortality risk among women with colorectal cancer in the NIH-AARP Diet and Health Study. [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 888. doi:10.1158/1538-7445.AM2015-888
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study
Authors: Michael W Konstan, Edward F McKone, Richard B Moss, Gautham Marigowda, Simon Tian, David Waltz, Xiaohong Huang, Barry Lubarsky, Jaime Rubin, Stefanie J Millar, David J Pasta, Nicole Mayer-Hamblett, Christopher H Goss, Wayne Morgan, Gregory S Sawicki
Journal: The Lancet Respiratory Medicine (2016)
Phase III, randomized, open-label study of triweekly versus biweekly docetaxel (T) as a treatment for advanced hormone-refractory prostate cancer (HRPC): Final analysis of the Finnish Uro-oncological Group Study 1-2003.
Authors: P. Kellokumpu-Lehtinen, U. Harmenberg, T. K. Joensuu, R. McDermott, P. Hervonen, C. Ginman, M. Luukkaa, P. Nyandoto, T. Luukkaala, H. Joensuu
Journal: Journal of Clinical Oncology (2011)

4527 Background: T administered at 3-week intervals is standard treatment for advanced HRPC. We compared 2-weekly to 3-weekly T as first-line chemotherapy of advanced HRPC (prior estramustine phosphate allowed). Methods: 361 pts were entered in this prospective, randomized multicenter trial from March 2004 to May 2009. 346 pts were eligible and received at least one T cycle. The pts were centrally randomly assigned to receive T i.v. either 75 mg/m² d1 q3 wks (tT) or 50 mg/m² d1 and d 14, q4 wks (bT). Prednisolon 10 mg/d was administered orally in both groups. The groups were well balanced with the WHO performance status, mean age (69.3 yrs, range 45-87 yrs vs. 68 yrs, range, 46-85 yrs), and the median serum PSA content at study entry (108.5 µg/L, range 11-1230 vs. 116 µg/L, range 12-1870, respectively). The primary end point was time to treatment failure (TTTF). The planned sample size was 348 pts (α 0.05, 1-ß 0.80, 2-sided log-rank test). Study identifier: NCT00255606. Results: The 346 eligible pts who received at least one dose of docetaxel (tT, 176; bT, 170) are included in the analysis. 1249 and 1051 T cycles were administered in the tT and bT groups, respectively. Serious adverse events were reported more often with the 3-weekly schedule (5.9 vs. 9.4 % of cycles, p=0.002). The median TTTF was longer in the bT group compared to tT (5.6 vs. 4.9 mos, respectively; p=0.016). PSA response was equally frequent in both groups (CR+PR 23%; SD 46%). Overall survival did not differ significantly between the 2 groups (median, 11.2 vs. 11.8 mos, respectively, p=0.164). Conclusions: T administered every 2 weeks was better tolerated than 3-weekly administration and resulted in a longer TTTF, but did not improve survival.
Clofarabine in Combination with a Standard Remission Induction Regimen (AraC and idarubicin) in Patients with Previously Untreated Intermediate and Bad Risk Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS):Phase I Results of An Ongoing Phase I/II Study of the EORTC-LG and GIMEMA(EORTC GIMEMA 06061/AML-14A trial)
Authors: Roelof Willemze, Petra Muus, Stijn J.M. Halkes, Giovanna Meloni, Stefan Suciu, Liv Meert, Jocelyne Flament, Matthias Karrasch, Marco Vignetti, Sergio Amadori, Theo M. de Witte, Jean-Pierre Marie
Journal: Blood (2011)