tbuckley/cabot-search huggingface dataset:
The proportion and characterization of patients with metastatic renal cell carcinoma who are never treated or have delayed treatment with targeted therapy: Results from a large prospective cohort.
Authors: Param Bains, Daniel Yick Chin Heng, Jennifer J. Knox, Georg A. Bjarnason, Christian K. Kollmannsberger, Sebastien J. Hotte, Anil Kapoor, Marie Vanhuyse, M. Neil Neil Reaume, Piotr Czaykowski, Denis Soulieres, Naveen S. Basappa, Olli Saarela, Lori Wood
Journal: Journal of Clinical Oncology (2015)

424 Background: The proportion and characterization of patients (pts) with metastatic renal cell carcinoma (mRCC) who never start or delay starting targeted therapy (TT) is unknown. It is important to understand and characterize these pts. Methods: Data from the Canadian Kidney Cancer information system (CKCis) database were utilized. CKCis data were collected prospectively from 14 REB-approved academic centers in Canada. The study population included pts with mRCC managed from 2006 (when VEGFR TT became available) to 2014. Results: 920 pts met the inclusion criteria, but 67 pts had &lt;6 months (mo) follow up and were excluded. Thus, 853 pts make up the study cohort with a median follow up of 21 mo. The cohort was divided into 3 groups: early (started TT within 6 mo), delayed (started TT after 6 mo), and never (never started TT). The groups consisted of 406 pts (47.6%), 182 pts (21.3%), and 265 pts (31.1%), respectively. In those that started TT, median time to initiation was 3.2 mo; 69% by 6 mo, 82% by 12 mo, 92% by 24 mo, and 99.7% by 5 yrs. Multiple baseline characteristics were determined, compared, and will be presented. On univariable analysis, pts never treated were older, had a longer interval from original diagnosis to metastases (mets), fewer metastatic sites, fewer liver mets, more lung-only mets, more metastectomies, and less radiation (RT). On Cox regression analysis, pts were less likely to initiate TT if they were older, had earlier year of diagnosis of mets, had metastectomy, never had RT, fewer sites of mets, and brain mets. Median survival from time of metastatic diagnosis was 1.53 yrs, 3.54 yrs, and 1.41 yrs in the early, delayed, and never treated groups, respectively. Conclusions: 31% of pts with mRCC never received TT in this cohort of pts treated in academic centers, which may underrepresent the reality in the community. Baseline characteristics in the delayed treatment group were better and likely represent a more indolent biology. More data on the untreated group will be presented as it comprises a heterogenous group of pts: potentially those lost to follow up, those treated with metastectomy, pts too ill with limited survival, and pts felt to have excellent outcomes without treatment.
Efficient In Vivo Liver-Directed Gene Editing Using CRISPR/Cas9
Authors: Kshitiz Singh, Hanneke Evens, Nisha Nair, Melvin Y. Rincón, Shilpita Sarcar, Ermira Samara-Kuko, Marinee K. Chuah, Thierry VandenDriessche
Journal: Molecular Therapy (2018)

In vivo tissue-specific genome editing at the desired loci is still a challenge. Here, we report that AAV9-delivery of truncated guide RNAs (gRNAs) and Cas9 under the control of a computationally designed hepatocyte-specific promoter lead to liver-specific and sequence-specific targeting in the mouse factor IX (F9) gene. The efficiency of in vivo targeting was assessed by T7E1 assays, site-specific Sanger sequencing, and deep sequencing of on-target and putative off-target sites. Though AAV9 transduction was apparent in multiple tissues and organs, Cas9 expression was restricted mainly to the liver, with only minimal or no expression in other non-hepatic tissues. Consequently, the insertions and deletion (indel) frequency was robust in the liver (up to 50%) in the desired target loci of the F9 gene, with no evidence of targeting in other organs or other putative off-target sites. This resulted in a substantial loss of FIX activity and the emergence of a bleeding phenotype, consistent with hemophilia B. The in vivo efficacy of the truncated gRNA was as high as that of full-length gRNA. Cas9 expression was transient in neonates, representing an attractive "hit-and-run" paradigm. Our findings have potentially broad implications for somatic gene targeting in the liver using the CRISPR/Cas9 platform.
The composite regulatory basis of the large X-effect in mouse speciation
Authors: Erica L. Larson, Sara Keeble, Dan Vanderpool, Matthew D. Dean, Jeffrey M. Good
Journal: Molecular Biology and Evolution (2016)

The disruption of meiotic sex chromosome inactivation (MSCI) has been proposed to be a major developmental mechanism underlying the rapid evolution of hybrid male sterility. We tested this idea by analyzing cell-specific gene expression across spermatogenesis in two lineages of house mice and their sterile and fertile reciprocal hybrids. We found pervasive disruption of sex chromosome gene expression in sterile hybrids at every stage of spermatogenesis. Failure of MSCI was developmentally preceded by increased silencing of autosomal genes, supporting the hypothesis that divergence at the hybrid incompatibility gene, Prdm9, results in increased rates of autosomal asynapsis which in turn triggers widespread silencing of unsynapsed chromatin. We also detected opposite patterns of postmeiotic overexpression or hyper-repression of the sex chromosomes in reciprocal hybrids, supporting the hypothesis that genomic conflict has driven functional divergence that leads to deleterious X–Y dosage imbalances in hybrids. Our developmental timeline also exposed more subtle patterns of mitotic misregulation on the X chromosome, a previously undocumented stage of spermatogenic disruption in this cross. These results indicate that multiple hybrid incompatibilities have converged on a common regulatory phenotype, the disrupted expression of the sex chromosomes during spermatogenesis. Collectively, these data reveal a composite regulatory basis to hybrid male sterility in mice that helps resolve the mechanistic underpinnings of the well-documented large X-effect in mice speciation. We propose that the inherent sensitivity of spermatogenesis to X-linked regulatory disruption has the potential to be a major driver of reproductive isolation in species with chromosomal sex determination.
Abstract 1169: Growth regulation of bladder cancer cells by compounds that affect glucose metabolism
Authors: Michael A. Lea, Charles desBordes
Journal: Cancer Research (2015)

Abstract The observation that cancer cells tend to exhibit enhanced rates of glycolysis presents a target for therapeutic regulation of cancer cell growth by molecules that regulate glucose metabolism. We have extended our earlier studies on colon cancer cells with an examination in bladder cancer cells of the action of an established inhibitor of PFKFB3, namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) as a single agent and in combination with other molecules that affect glycolysis and proliferation. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB-3) is an enzyme regulating glycolysis in many tumor cells. Cell growth was monitored by staining with sulforhodamine B. Of the 8 cell lines examined, growth was most rapid in the T24 and UM-UC-3 bladder cancer cells. The slowest growth was seen with RT4, TCCSUP and HT1197 cells while intermediate growth rates were observed with 5637, HT1376, and SW780 cells. Glucose uptake from the medium and acidification of the medium over a 72-hour incubation tended to correlate with growth rate. Thus the greatest changes were seen with the T24 and UM-UC-3 cell lines and the least change was seen with RT4 and TCCSUP cells. Growth was inhibited when glutamine was omitted from the medium but growth was blocked in the absence of glucose except for RT4 cells in which growth was inhibited more in the absence of glutamine. Treatment with 10 μM 3PO as a single agent for 72 hours caused average growth inhibition in the range of 25-50% without apparent relationship to the control growth rates of the cell lines. Additive inhibitory effects on growth were observed when cells were coincubated with 3PO and either 1 mM 2-deoxyglucose, 50 μM phenformin or 1 mM butyrate. In addition to being growth inhibitory, butyrate also caused significant induction of alkaline phosphatase activity in some cell lines. When cells were incubated with phenformin as a single agent, there was generally an increased acidification of the medium that was diminished by coincubation with 3PO. In conclusion, 3PO was an inhibitor of proliferation of human bladder cancer cells and may be a useful agent in combination with other drugs that inhibit bladder cancer cell proliferation. Citation Format: Michael A. Lea, Charles desBordes. Growth regulation of bladder cancer cells by compounds that affect glucose 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 1169. doi:10.1158/1538-7445.AM2015-1169
Final Results from a Phase 2 Study of Pracinostat in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML)
Authors: Guillermo Garcia-Manero, Ehab Atallah, Samer K Khaled, Martha Arellano, Mrinal M Patnaik, Todd A Butler, Carla Ashby, Bruno C. Medeiros
Journal: Blood (2015)
High (95%) Response Rates in Relapsed/Refractory Mantle Cell Lymphoma after R-HCVAD Alternating with R-Methotrexate/Cytarabine (R-M-A).
Authors: Jorge Enrique Romaguera, Luis E. Fayad, Michael Wang, Fernando Cabanillas, Fredrick Hagemeister, Peter McLaughlin, Alma Rodriguez, Anas Younes, Sattva Neelapu, Andre H. Goy, Virginia Beasley, Larry Kwak
Journal: Blood (2005)
320. Transcriptional Silencing via Synthetic DNA Binding Protein Lacking Canonical Repressor Domains as a Potent Tool to Generate Therapeutics
Authors: Salvatore Botta, Elena Marrocco, Nicola de Prisco, Fabiola Curion, Mario Renda, Martina Sofia, Mariangela Lupo, Maria Laura Bacci, Carlo Gesualdo, Settimio Rossi, Francesca Simonelli, Enrico Maria Surace
Journal: Molecular Therapy (2016)

Transcription factors (TFs) function by the combined activity of their DNA-binding domains (DBDs) and effector domains (EDs). Here we show that in vivo delivery of an engineered DNA-binding protein uncoupled from the repressor domain entails complete and gene-specific transcriptional silencing. To silence RHODOPSIN (RHO) gain-of-function mutations, we engineered a synthetic DNA-binding protein lacking canonical repressor domains and targeted to the regulatory region of the RHO gene. AAV-mediate retinal delivery at a low dose (AAV2/8-CMV-ZF6-DBD, 1×10e10 vector genomes, vg) in the porcine retina resulted in selective transcriptional silencing of RHO expression. The rod photoreceptors (the RHO expressing cells) transduced cells when isolated by FACS-sorting showed the remarkable 90% RHO transcriptional repression. To evaluate genome-wide transcriptional specificity, we analyzed the porcine retina transcriptome by RNA sequencing (RNA-Seq). The differentially expressed genes (DEGs) analysis showed that only 19 genes were perturbed. In this study, we describe a system based on a synthetic DNA binding protein enabling targeted transcriptional silencing of the RHO gene by in vivo gene transfer. The high rate of transcriptional silencing occurring in transduced cells supports applications of this regulatory genomic interference with a synthetic trans-acting factor for diseases requiring gene silencing in a large number of affected cells, including for instance a number of neurodegeneration disorders. The result support a novel mode of gene targeted silencing with a DNA-binding protein lacking intrinsic activity.
Dementia and Alzheimer's Disease among Older Kidney Transplant Recipients
Authors: Mara A. McAdams-DeMarco, Sunjae Bae, Nadia Chu, Alden L. Gross, Charles H. Brown, Esther Oh, Paul Rosenberg, Karin J. Neufeld, Ravi Varadhan, Marilyn Albert, Jeremy Walston, Dorry L. Segev
Journal: Journal of the American Society of Nephrology (2016)

Older patients with ESRD who receive a kidney transplant (KT) may develop post-KT dementia and Alzheimer's disease (AD) associated with their long-standing kidney disease and/or neurotoxic immunosuppressant agents. To investigate this possibility, we studied 40,918 older (aged ≥55 years) KT recipients (January 1, 1999 to December 31, 2011) linked to Medicare claims through the US Renal Data System. We estimated dementia and AD risk (cumulative incidence) and studied factors associated with these sequelae using competing risks models. We estimated the risk of death-censored graft loss and mortality after developing dementia or the AD subtype of dementia, separately, using adjusted Cox proportional hazards models. Older recipients had a 10-year dementia risk ranging from 5.1% for recipients aged 55–60 years to 17.0% for recipients aged ≥75 years; 10-year AD risk ranged from 1.0% to 6.7%, respectively. The strongest predictors for dementia and AD were older recipient age and pretransplant diabetes. The 10-year graft loss risk was 28.8% for those who did not develop dementia and 43.1% for those who did, and the corresponding mortality risks were 55.7% and 89.9%, respectively. Older recipients with dementia had a 1.52-fold (95% confidence interval, 1.39 to 1.68) increased risk of graft loss and a 2.38-fold (95% confidence interval, 2.26 to 2.49) increased risk of mortality. We observed similar results for AD. We conclude that older KT recipients have a high risk of post-KT dementia and AD, and these sequelae associate with a profound effect on patient and graft survival.
25. Intranasal Gene Delivery of AAV Iduronidase: An Effective and Non-Invasive Approach for Treatmentof CNS Disease in a Murine Model of MPS Type I
Authors: Lalitha Belur, Megan Buckvold, Kelly M. Podetz-Pedersen, Maureen Riedl, Lucy Vulchanova, Leah Hanson, Carolyn Fairbanks, Karen Kozarsky, William H. Frey, Walter C. Low, R. Scott Mclvor
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis type I (MPS I) is a progressive, multisystemic, inherited metabolic disease caused by deficiency of alpha-L-iduronidase (IDUA). The most severe form of this disease (Hurler syndrome) results in death by age 10. Current treatments for this disease are ineffective in treating CNS disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. Our goal is to supplement current therapy, and treat CNS manifestations of the disease, by AAV-mediated gene delivery and expression of IDUA. We have taken a non-invasive and effective approach to the treatment of CNS disease by intranasal administration of an IDUA-encoding AAV9 vector. Adult IDUA-deficient mice were immunotolerized at birth with human iduronidase, to prevent anti-IDUA immune response, and at 3 months of age were infused intranasally with AAV9-IDUA vector. Animals sacrificed 3 months post-infusion exhibited IDUA enzyme activity levels that were 100-fold that of wild type in the olfactory bulb, with wild type levels of enzyme restored in all other parts of the brain. Neurocognitive testing using the Barnes maze demonstrated that treated IDUA-deficient mice were not different from normal control animals, while untreated IDUA-deficient mice exhibited a significant learning deficit. There was strong IDUA immunofluorescence staining observed in tissue sections of the nasal epithelium and olfactory bulb, but no staining was observed in other portions of the brain. This indicates that the widespread distribution of IDUA enzyme most likely was the result of enzyme diffusion from sites of transduction and IDUA expression in the olfactory bulb and the nasal epithelium into deeper areas of the brain. In order to increase access, delivery and vector distribution throughout the brain, IDUA-deficient animals were pretreated with intranasal infusions of an absorption enhancer. At different time points following pretreatment, animals were infused intranasally with AAV9 or AAVrh10 vector encoding IDUA. Animals were sacrificed at 2 months post-infusion, brains microdissected, and assayed for IDUA enzyme activity, clearance of glycosaminoglycans, and immunofluorescence staining for IDUA and GFP. This novel, non-invasive strategy for intranasal AAV9-IDUA administration could potentially be used to treat CNS manifestations of MPS I.
The Clinical and Therapeutic Drug Monitoring of Oral and Intravenous Busulfan in Patients with Acute Leukemia That Underwent to Stem Cell Transplantation with a Test Dose of Busulfan
Authors: Iracema Esteves, Juliana F Fernandes, Andreza Feitosa Ribeiro, Fabio P S Santos, Ricardo Helman, Claudio Castro Junior, Vinicius R. P. Mattos, Andrea Tiemi Kondo, Adriana Seber, Jose Salvador Rodrigues Oliveira, José Carlos Barros, Vergilio Antonio Renzi Colturato, Nelson Hamerschlak, Fabio Rodrigues Kerbauy
Journal: Blood (2014)
Abstract 3251: Regulation of TNBC kinome by the metastasis suppressor Raf kinase inhibitory protein (RKIP)
Authors: Ali E. Yesilkanal, Casey Frankenberger, Daniel Rabe, Gary L. Johnson, Marsha R. Rosner
Journal: Cancer Research (2015)

Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with very low survival rates. Metastatic progression of tumors is the major cause of death in TNBC patients. Metastatic spread of tumor cells is generally associated with resistance to therapy and poor prognosis. Therefore, there is a clinical need for understanding the molecular and cellular basis of metastasis and developing effective therapies against metastatic progression. However, since metastasis is a multi-step process, unraveling its complexity is a major challenge. One effective way of tackling this question is to study natural blockers of the metastatic process, metastasis suppressors, and identify the mechanisms by which they regulate metastasis. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor in TNBC, which acts as a homeostatic factor that regulates kinase activity. RKIP blocks invasion in vitro and experimental metastasis in vivo. Therefore, RKIP constitutes a powerful tool for studying metastatic signaling pathways in cancer cells. RKIP is known to regulate the activity of certain kinases such as Raf-1, GRK2, NIK, and GSK3β, affecting major pathways such as MAPK, NFκB, and WNT. However, our preliminary data suggests that RKIP affects a much larger part of the TNBC kinome. Using proteomics approaches, we have identified putative novel kinase targets of RKIP, and used bioinformatics analysis to build RKIP-regulated signaling networks. Elucidating RKIP's function at a systems level will reveal the interplay between key metastatic signaling cascades and potentially identify novel anti-metastatic target combinations in TNBCs. Citation Format: Ali E. Yesilkanal, Casey Frankenberger, Daniel Rabe, Gary L. Johnson, Marsha R. Rosner. Regulation of TNBC kinome by the metastasis suppressor Raf kinase inhibitory protein (RKIP). [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 3251. doi:10.1158/1538-7445.AM2015-3251
Outcomes of Hematopoietic Cell Transplantation in Patients with Refractory Acute Myeloid Leukemia
Authors: Annie Im, Navkiranjit Gill, Diana Cunningham, Mounzer Agha, Anastasios Raptis, Jing-Zhou Hou, Robert L. Redner, Julie Phillips, Michael Boyiadzis
Journal: Blood (2012)
Physical activity and prostate gene expression in men with low-risk prostate cancer.
Authors: Mark Jesus Mendoza Magbanua, Erin L Richman, Eduardo V Sosa, Lee Jones, Jeffrey Simko, Katsuto Shinohara, Christopher M. Haqq, Peter Carroll, June M. Chan
Journal: Journal of Clinical Oncology (2012)

189 Background: Physical activity (PA), in particular longer duration or higher intensity, may reduce the risk of PCa progression and PCa-specific mortality in men diagnosed with clinically localized PCa. However, the molecular mechanism(s) by which PA exerts its protective effect in the prostate remains unknown. We examined the correlation of PA and gene expression patterns in men with low risk prostate cancer who elected to undergo active surveillance. Methods: Morphologically normal prostate tissue was obtained from men who subsequently participated in a clinical trial focused on nutritional supplements (previously published microarray dataset #GSE27140). Of the original sample (n=84), 70 completed a brief PA questionnaire and were dichotomized based usual PA [e.g. any vigorous PA (yes/no), 3+ h/wk vigorous PA (yes/no)]. Differential expression and pathway (gene set) analyses between groups were performed using Significance Analysis of Microarrays. Genes and gene sets with a false discovery rate ≤0.10 and 0.20 were considered significant, respectively. Results: Gene expression analysis detected 184 significant genes that were differentially expressed between men who performed vigorous PA for 3+ h/wk (n=23) and those who did not (n= 47). Up-regulated genes included the known tumor suppressors, BRCA1 and BRCA2. Furthermore, pathway analysis revealed that cell cycle and DNA repair pathways were positively modulated in men who participated in 3+h/wk vigorous PA vs. not. Consistent with the data on vigorous PA and clinical outcomes in men with PCa, the duration of vigorous PA was important; there were no significant genes detected when comparing men who participated in any vigorous PA to men who did none. Conclusions: Prostate gene expression and pathway analyses revealed candidate genes and in vivo pathways that may be modulated by participating in 3+ h/wk of vigorous PA. These data provide mechanistic insight into how 3+ h/wk of vigorous PA may offer PCa-specific benefits. Furthermore, understanding the molecular mechanisms by which such PA affects normal prostate gene expression may aid the development of strategies to prevent or delay PCa progression.
A Randomized Trial of Rabbit Anti-Thymocyte Globulin, Given on Day+7 after Alternative Donor Transplants.
Authors: Andrea Bacigalupo, Teresa Lamparelli, Fabio Ciceri, Fedro Peccatori, Anna Locasciulli, Ignazio Majolino, Paolo Di Bartolomeo, Giuseppe Milone, Patrizio Mazza, Pasquale Lacopino, Nicoletta Sacchi, Maria Teresa van Lint
Journal: Blood (2006)