tbuckley/cabot-search huggingface dataset:
Incremental Value of 18F-Fluorocholine PET/CT in the Localization of Double Parathyroid Adenomas
Authors: Paul Lalire, Sang Ly, Sophie Deguelte, Martine Patey, David Morland
Journal: Clinical Nuclear Medicine (2016)

A 73-year-old man displaying primary hyperparathyroidism with severe hypercalcemia (Ca: 4.1 mmol/l, PTH > 600 pmol/l) was referred for preoperative localization of a parathyroid adenoma. Tc-pertechnetate and Tc-sestaMIBI dual tracer scintigraphy displayed a mild focal uptake in the projection of the right thyroid lobe with negative ultrasonography. F-Fluorocholine PET/CT was quickly performed considering this discrepancy and not only confirmed the scintigraphic findings but also revealed a second contralateral focus of increased uptake, both later confirmed by operative consideration (the two other parathyroid glands are considered normal by the surgeon), pathology, and intraoperative parathyroid hormone assessment.
Abstract B73: Pancreatic stellate cell heterogeneity in cancer
Authors: Daniel Öhlund, Abram Handly-Santana, Ela Elyada, Giulia Biffi, David A. Tuveson
Journal: Cancer Research (2016)

Abstract Paracrine interactions between pancreatic stellate cells (PSCs) and tumor cells play key roles in pancreatic cancer tumorigenesis. However, attempts to therapeutically target the PSCs have implied that PSCs may also restrain tumor growth, raising the possibility of diverse and dynamic pathophysiological roles of these cells in cancer. In order to gain a deeper understanding of the functional heterogeneity found among PSCs, we have developed an organotypic co-culture system that allows the study of functional interactions between pancreatic tumor-derived organoids and PSCs in a three-dimensional basement membrane matrix (Matrigel). PSCs embedded in Matrigel acquire a quiescent phenotype and restore their vitamin A droplets similar to PSCs found in healthy pancreata in vivo. In co-culture the PSCs proliferate, form lattices around the organoids, and secrete extracellular matrix proteins and inflammatory cytokines. In turn, the organoids proliferate more rapidly in co-culture with PSCs compared to their mono-cultured counterparts, as well as survive passaging in reduced media conditions. Furthermore, we show that PSCs can differentiate into two distinct subtypes with different phenotypic features depending on the spatial proximity to the co-cultured organoids. PSCs found in direct contact with tumor cells express higher levels of smooth muscle actin (SMA), while PSCs that are more distant from the tumor cells show low SMA expression and gain a secretory phenotype. The secreted factors from this subtype of PSCs activate signaling pathways important for survival and proliferation in tumor organoids. We demonstrate that these two subtypes are mutually exclusive, and can both be found in vivo with similar spatial distribution as seen in the co-culture system. Taken together, we have identified two subtypes of PSCs present in pancreatic cancer with potentially different pathophysiological functions. Preferentially targeting one of these subtypes in future clinical trials may positively affect patient outcomes. Citation Format: Daniel Öhlund, Abram Handly-Santana, Ela Elyada, Giulia Biffi, David A. Tuveson.{Authors}. Pancreatic stellate cell heterogeneity in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B73.
Abstract 4372: Phosphodiesterase 10A inhibition suppresses lung tumor cell growth by activating PKG to inhibit ras and Wnt signaling
Authors: Bing Zhu, Kevin Lee, Joshua Canzoneri, Veronica Ramirez-Alcantara, Sara Sigler, Bernard Gary, Ethan Butler, Adam Keeton, Xi Chen, Michael Boyd, Gary Piazza
Journal: Cancer Research (2015)

Abstract We recently reported that phosphodiesterase 10A (PDE10) is overexpressed in colon tumors and essential for colon tumor cell growth (Li et al., Oncogene 2014), but a role in lung cancer has not been well studied. Human non-small cell lung cancer (NSCLC) cell lines were found to express appreciably higher PDE10 levels compared with normal airway epithelial cells, while silencing of PDE10 expression with siRNA or inhibition of PDE10 activity with small molecule inhibitors selectively inhibits NSCLC cell growth. Here we study the mechanism by which PDE10 inhibitors suppress NSCLC cell growth. At concentrations effective for inhibiting NSCLC cell growth, the PDE10 inhibitor, PQ10 rapidly increases intracellular cGMP levels as determined by a luminescence biosensor assay. Within the same concentration range and time period, PQ10 activates PKA and PKG, demonstrated by an increase in phosphorylation of the substrate, VASP at Ser157 and Ser239, respectively. Under the same conditions, PQ10 suppresses the phosphorylation of Erk1/2 (Thr202/Tyr204), MEK1/2 (Ser217/Ser221) and down-stream p90RSK (Ser380). Similarly, PQ10 increases the phosphorylation of β-catenin at Ser552, but showed no effect on phospho-Ser675 levels. After longer durations of treatment, PQ10 reduces β-catenin levels, as well as proteins that are regulated by β-catenin-dependent TCF/LEF-transcriptional activity, such as survivin and cyclin D1. These effects were mimicked by a novel structurally unrelated PDE10 inhibitor, ADT-020 that selectively inhibits the growth of NSCLC cells and increases cGMP levels in a manner similar to PQ10. ADT-020 also activates PKG in NSCLC cells demonstrated by higher phospho-Ser239 VASP levels and lower β-catenin and survivin levels. These observations suggest that PDE10 inhibition and activation of PKG can simultaneously suppress ras and Wnt signaling that are essential for lung tumor cell growth. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza). Citation Format: Bing Zhu, Kevin Lee, Joshua Canzoneri, Veronica Ramirez-Alcantara, Sara Sigler, Bernard Gary, Ethan Butler, Adam Keeton, Xi Chen, Michael Boyd, Gary Piazza. Phosphodiesterase 10A inhibition suppresses lung tumor cell growth by activating PKG to inhibit ras and Wnt signaling. [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 4372. doi:10.1158/1538-7445.AM2015-4372
Association of State Recreational Marijuana Laws With Adolescent Marijuana Use
Authors: Magdalena Cerdá, Melanie Wall, Tianshu Feng, Katherine M. Keyes, Aaron Sarvet, John Schulenberg, Patrick M. O’Malley, Rosalie Liccardo Pacula, Sandro Galea, Deborah S. Hasin
Journal: JAMA Pediatrics (2016)

<h3>Importance</h3> Historical shifts are occurring in marijuana policy. The effect of legalizing marijuana for recreational use on rates of adolescent marijuana use is a topic of considerable debate. <h3>Objective</h3> To examine the association between the legalization of recreational marijuana use in Washington and Colorado in 2012 and the subsequent perceived harmfulness and use of marijuana by adolescents. <h3>Design, Setting, and Participants</h3> We used data of 253 902 students in eighth, 10th, and 12th grades from 2010 to 2015 from Monitoring the Future, a national, annual, cross-sectional survey of students in secondary schools in the contiguous United States. Difference-in-difference estimates compared changes in perceived harmfulness of marijuana use and in past-month marijuana use in Washington and Colorado prior to recreational marijuana legalization (2010-2012) with postlegalization (2013-2015) vs the contemporaneous trends in other states that did not legalize recreational marijuana use in this period. <h3>Main Outcomes and Measures</h3> Perceived harmfulness of marijuana use (great or moderate risk to health from smoking marijuana occasionally) and marijuana use (past 30 days). <h3>Results</h3> Of the 253 902 participants, 120 590 of 245 065(49.2%) were male, and the mean (SD) age was 15.6 (1.7) years. In Washington, perceived harmfulness declined 14.2% and 16.1% among eighth and 10th graders, respectively, while marijuana use increased 2.0% and 4.1% from 2010-2012 to 2013-2015. In contrast, among states that did not legalize recreational marijuana use, perceived harmfulness decreased by 4.9% and 7.2% among eighth and 10th graders, respectively, and marijuana use decreased by 1.3% and 0.9% over the same period. Difference-in-difference estimates comparing Washington vs states that did not legalize recreational drug use indicated that these differences were significant for perceived harmfulness (eighth graders: % [SD], −9.3 [3.5];<i>P</i> = .01; 10th graders: % [SD], −9.0 [3.8];<i>P</i> = .02) and marijuana use (eighth graders: % [SD], 5.0 [1.9];<i>P</i> = .03; 10th graders: % [SD], 3.2 [1.5];<i>P</i> = .007). No significant differences were found in perceived harmfulness or marijuana use among 12th graders in Washington or for any of the 3 grades in Colorado. <h3>Conclusions and Relevance</h3> Among eighth and 10th graders in Washington, perceived harmfulness of marijuana use decreased and marijuana use increased following legalization of recreational marijuana use. In contrast, Colorado did not exhibit any differential change in perceived harmfulness or past-month adolescent marijuana use following legalization. A cautious interpretation of the findings suggests investment in evidence-based adolescent substance use prevention programs in any additional states that may legalize recreational marijuana use.
Mitochondrial targeting of FGF-2 antisense proteins and their function in cancer cell proliferation
Authors: Shuocheng Zhang, Paul R. Murphy
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2864 

Mammalian cells have evolved a variety of defence mechanisms to protect the integrity of the mitochondrial and nuclear genomes from oxidative damage. These include several members of the Nudix hydrolase superfamily of enzymes, characterized by a loop-helix-loop nudix motif involved in substrate binding and catalysis. Loss of function of nudix genes such as OGG1, MYH and MTH1 has been implicated in mutagenesis and tumorigenesis of lung, colorectal and liver cancers. The highly conserved FGF-2 antisense gene, fgf-as, encodes a novel nudix motif protein called GFG. We recently showed that rat GFG has anti-mutator activity in vitro, and that GFG expression was down regulated in pituitary, esophageal and endometrial cancer tissues. In the present study we investigated the subcellular localization of alternatively spliced GFG isoforms in rat and human cells. At least 3 GFG isoforms are produced by alternative splicing ([Fig 1][1]). The largest isoform contains a putative mitochondrial targetting signal peptide (MTSP) in the N-terminus. To confirm mitochondrial targeting of GFG, full-length and truncated rat and human GFG:GFP constructs were generated. Their subcellular localisation in stably transfected C6 glioma cells was monitored with confocal laser scanning microscopy. Our results indicate that GFP fusions of full-length human or rat GFG proteins bearing the predicted MTSP were targeted highly specifically to mitochondria. Furthermore, an N-terminal 75 aa fragment of rat GFG, containing the MTSP, can efficiently direct GFP to mitochondria. Following deletion of the N-terminal MTSP of rat GFG, the GFP fusion protein was localised in cytoplasm and nucleus. Similarly, the GFP fusion protein of human GFG isoform C, which does not contain the putative MTSP, localised exclusively in cytoplasm and nucleus. These observations indicate that selective trafficking of GFG isoforms to different subcellular compartments may be of central importance to the anti-mutator activity in mitochondria and cytoplasm and/or nucleus. The molecular action of GFG in in rat and human cancer cells is currently under investigation. (supported by the CIHR).



![Figure][2]  [1]: #F1
 [2]: pending:yes
A Critical Role for PIM2 Kinase in Multiple Myeloma Through NF-κB Activation
Authors: Veerendra Munugalavadla, Leanne Berry, Jae Chang, Geoffrey Del Rosario, Jake Drummond, Changchun Du, Karen Fitzgerald, Lori S Friedman, Stephen E Gould, Heather Maecker, John Moffat, Dionysos Slaga, Xiaojing Xiaojing, Kristina West, Shang-Fan Yu, Allen J. Ebens
Journal: Blood (2011)
PTU-057 Predictors of response to combination therapy for chronic hepatitis C: the Leeds experience
Authors: A C Ford, S A Sheridan, C M Wigglesworth, J Rehman, M A Aldersley, M H Davies, C E Millson, R L Jones
Journal: Gut (2010)

<h3>Introduction</h3> Combination therapy for chronic hepatitis C (CHC) achieves sustained viral response (SVR) in randomised trials. We studied factors predicting SVR 6 months after the end of treatment (undetectable viral load by PCR) in normal clinical practice, in a large cohort of CHC patients treated in a single tertiary referral centre in Leeds, UK. <h3>Methods</h3> Data for individuals receiving combination therapy for CHC were collected prospectively between February 2001 and May 2008. Age, gender, ethnicity, type of interferon (α-2a or 2b), genotype, presence of cirrhosis, body mass index (BMI), alcohol use (none vs any), serum ferritin, and history of intravenous drug use (IVDU) or psychiatric illness were collected prior to commencing therapy. Early discontinuation of therapy was also recorded. The association between these variables and achieving an SVR was explored by univariate and multivariate analysis, with ORs and 95% CIs. Data from individuals being re-treated for CHC were not analysed. Individuals defaulting follow-up with no SVR data at 6 months were classed as treatment failures. <h3>Results</h3> During the study period 394 individuals with CHC commenced combination therapy (257 (65%) male, mean age 42 years (range 21–74)). After univariate analysis SVR at 6 months was significantly more likely in younger patients (OR per year 0.96, 95% CI 0.94 to 0.98), with interferon α-2b (OR 1.61, 95% CI 1.00 to 2.58), in genotype 2 and 3 compared with genotype 1 (OR 3.52, 95% CI 1.47 to 8.44, and OR 3.51, 95% CI 2.23 to 5.54, respectively), and significantly less likely in those with biopsy-proven cirrhosis (OR 0.24, 95% CI 0.15 to 0.39), in those consuming any alcohol (OR 0.35, 95% CI 0.22 to 0.55), those with serum ferritin &gt;250 (OR 0.26, 95% CI 0.15 to 0.46), and those discontinuing therapy early (OR 0.22, 95% CI 0.13 to 0.39). Following multivariate analysis effect of genotype, alcohol use, presence of cirrhosis, and early discontinuation of therapy on SVR remained significant. Gender, ethnicity, BMI, and prior history of IVDU or psychiatric illness had no effect on SVR at 6 months in any of our analyses. <h3>Conclusion</h3> Data from this large cohort of patients with CHC treated with combination therapy demonstrate lower SVR rates in those consuming alcohol and those with cirrhosis. The former should be advised to cease consuming alcohol prior to embarking on therapy, and the latter should be warned of the reduced likelihood of successful therapy. A prior history of IVDU or psychiatric illness should not preclude consideration of combination therapy.
Pharmacokinetics and Pharmacodynamics of High Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and down Syndrome: a Case Cohort Study.
Authors: T. Buitenkamp, R. Mathot, A. Vulto, A. Veerman, E. van Wering, R. Pieters, M. Van Den Heuvel, Christian M Zwaan
Journal: Blood (2008)
M2 Macrophage Infiltration Is Closely Associated with Poor Prognosis for Adult T-Cell Leukemia/Lymphoma (ATLL),
Authors: Daisuke Niino, Yoshihiro Komohara, Yoshizo Kimura, Masanori Takeuchi, Hiroaki Miyoshi, Maki Yoshida, Ayako Ichikawa, Yasuo Sugita, Motohiro Takeya, Masahiro Kikuchi, Shigeo Nakamura, Koichi Ohshima
Journal: Blood (2011)
334. Improved MegaTAL Endonuclease Engineering Strategy for Gene Modification Applications
Authors: Yupeng Wang, Iram F. Khan, Courtnee Clough, Andrew M. Scharenberg, David J. Rawlings
Journal: Molecular Therapy (2015)

MegaTALs (MTALs) comprise a novel rare cutting endonuclease platform that couples a transcription activator-like effector (TALE) DNA binding domain with a homing endonuclease (HE) cleavage domain. MTALs are well suited for clinical translation due to their compact size coupled with high cleavage efficacy and specificity in gene modification applications. However, neither the relative contribution of the TALE domain vs. HE specificity to MTAL in vivo cleavage activity, nor the optimal strategy for MTAL engineering, have been rigorously explored. In the current study, we engineered multiple HE I-Anil variants with different properties, targeted to recognize a unique site in the human Bruton's tyrosine kinase (BTK) gene using a yeast surface display-based high throughput selection system. These BTK-Ani variants were combined with a TALE DNA binding domain containing an 11 repeat variable diresidue (RVD) array recognizing a specific sequence upstream of the BTK target site. The in vivo cleavage efficacy of this series of BTK MTAL enzymes was tested in a mammalian cell line report system. Here, we demonstrate that the turnover rate (Kcat) of the HE represents the most important contributing factor for MTAL activity in cellulo. This finding contrasts with activity profiling of HEs alone, where HE binding affinity and in vitro cleavage activity represent the most important factors predicting in vivo activity. Based on this observation, we optimized our engineering strategy to directly select for HE variants with higher Kcat activity. This modification significantly improved the post-selection output leading to engineered BTK MTALs with higher in vivo enzyme activity. Our emerging data demonstrates that the MTAL platform facilitates high rates of homology-directed-repair in primary human hematopoietic cells. Thus, this improved engineering platform should facilitate rapid development of new reagents for clinical genome editing applications.
Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire
Authors: David Y. Oh, Jason Cham, Li Zhang, Grant Fong, Serena S. Kwek, Mark Klinger, Malek Faham, Lawrence Fong
Journal: Cancer Research (2016)

While immune checkpoint blockade elicits efficacious responses in many patients with cancer, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAEs are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T-cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T-cell repertoire in IRAE patients compared with patients without IRAEs. Specifically, ipilimumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T-cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T-cell numbers relative to patients without IRAEs. Prostate-specific antigen responses to ipilimumab were also associated with increased T-cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for patients with cancer. Cancer Res; 77(6); 1322-30. ©2016 AACR.
Association of MicroRNA Expression Profiles with Karyotype in Acute Myeloid Leukaemias Revealed by Real-Time PCR and In Situ Hybridisation.
Authors: Amanda Dixon-McIver, Phil East, Charles A. Mein, Jean-Baptiste Cazier, Gael Molloy, Tracy Chaplin, T. Andrew Lister, Bryan Young, Silvana Debernardi
Journal: Blood (2007)
Low Pre-Test Probability Scores Are Not Sufficient to Exclude Heparin-Induced Thrombocytopenia in Critically Ill Patients
Authors: Noppacharn Uaprasert, Benjaporn Akkawat, Rattaporn Vichitratchaneekorn, Chantiya Chanswangphuwana, Ponlapat Rojnuckarin
Journal: Blood (2015)
REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells
Authors: Anantha L. Marisetty, Sanjay K. Singh, Tran N. Nguyen, Cristian Coarfa, Bin Liu, Sadhan Majumder
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is one of the most common, aggressive, and invasive human brain tumors. There are few reliable mechanism-based therapeutic approaches for GBM patients. The transcriptional repressor RE1 silencing transcriptional factor (REST) regulates the oncogenic properties of a class of GBM stem-like cells (high-REST [HR]-GSCs) in humans. However, it has been unclear whether REST represses specific targets to regulate specific oncogenic functions or represses all targets with overlapping functions in GSCs. We used genome-wide, biochemical, and mouse intracranial tumorigenic assays to identify and determine functions of microRNA (miR) targets of REST in 2 independent HR-GSC lines. Here we show that REST represses 2 major miR gene targets in HR-GSCs: miR-203, a new target, and miR-124, a known target. Gain of function of miR-124 or miR-203 in HR-GSCs increased survival in tumor-bearing mice. Importantly, the increased survival of tumor-bearing mice caused by knockdown of REST in HR-GSCs was reversed by double knockdown of REST and either miR-203 or miR-124, indicating that these 2 miRs are critical tumor suppressors that are repressed in REST-mediated tumorigenesis. We further show that while miR-124 and the REST–miR-124 pathways regulate self-renewal, apoptosis and invasion, miR-203 and the REST–miR-203 pathways regulate only invasion. We further identify and validate potential mRNA targets of miR-203 and miR-124 in REST-mediated HR-GSC tumor invasion. These findings indicate that REST regulates its miR gene targets with overlapping functions and suggest how REST maintains oncogenic competence in GSCs. These mechanisms could potentially be utilized to block REST-mediated GBM tumorigenesis.
Redefining the pathways of care: the patient journey
Authors: C. Di Nunzio, P. Mordenti, D.L. Capuano, A. Soriani, L. Zanlari, R. Achilli, M.L. Galli, E. Marazzi, S. Gandolfi, B. Granelli, D. Terzoni, G. Civardi, L. Cavanna
Journal: Annals of Oncology (2015)