tbuckley/cabot-search huggingface dataset:
Abstract POSTER-BIOL-1317: Releasing the brakes on ovarian cancer cell survival: epigenetic suppression of RGS10 in ovarian cancer chemoresistance
Authors: Shelley Hooks
Journal: Clinical Cancer Research (2015)

Abstract G-protein signaling pathways promote cell survival, which is aberrantly enhanced in chemoresistant ovarian cancer. Regulator of G-protein Signaling (RGS) proteins limit the strength of G-protein signaling, and therefore indirectly control cell survival. We have previously shown that RGS10 suppresses ovarian cancer cell growth and limits survival in the presence of cytotoxic chemotherapeutic drugs. Further, we have shown that RGS10 expression is suppressed in cell models of ovarian cancer chemoresistance, suggesting that ovarian cancer cells silence RGS10 expression to release the brakes on their growth and survival. However, the mechanisms governing RGS10 expression in ovarian cancer cells are poorly understood. In this study, we fully investigate the molecular mechanism of RGS10 suppression in ovarian cancer acquired chemoresistance, revealing key roles for epigenetic regulation by DNA hypermethylation and histone deacetylation. Pharmacological inhibition of DNA methyl-transferases (DNMTs) increases RGS10 expression in chemoresistant ovarian cancer cells, suggesting potential regulation by DNA methylation. Further, bisulfite sequencing analysis identified a region of the RGS10-1 promoter with significantly enhanced DNA methylation in chemoresistant A2780-AD cells relative to parental A2780 cells. More marked differences are observed in histone acetylation of the RGS10-1 promoter. Acetylated histone H3 associates with the RGS10-1 promoter was significantly lower in A2780-AD cells compared to parental cells, with a corresponding increase in histone deacetylase (HDAC) enzyme association. Further, both HDAC1 and DNMT1 exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 cooperatively contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance. Citation Format: Shelley Hooks, PhD. Releasing the brakes on ovarian cancer cell survival: epigenetic suppression of RGS10 in ovarian cancer chemoresistance [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1317.
Can we predict the outcome for people with patellofemoral pain? A systematic review on prognostic factors and treatment effect modifiers
Authors: M Matthews, M S Rathleff, A Claus, T McPoil, R Nee, K Crossley, B Vicenzino
Journal: British Journal of Sports Medicine (2016)

Background Patellofemoral pain (PFP) is a multifactorial and often persistent knee condition. One strategy to enhance patient outcomes is using clinically assessable patient characteristics to predict the outcome and match a specific treatment to an individual. Aim A systematic review was conducted to determine which baseline patient characteristics were (1) associated with patient outcome (prognosis); or (2) modified patient outcome from a specific treatment (treatment effect modifiers). Methods 6 electronic databases were searched (July 2016) for studies evaluating the association between those with PFP, their characteristics and outcome. All studies were appraised using the Epidemiological Appraisal Instrument. Studies that aimed to identify treatment effect modifiers underwent a checklist for methodological quality. Results The 24 included studies evaluated 180 participant characteristics. 12 studies investigated prognosis, and 12 studies investigated potential treatment effect modifiers. Important methodological limitations were identified. Some prognostic studies used a retrospective design. Studies aiming to identify treatment effect modifiers often analysed too many variables for the limiting sample size and typically failed to use a control or comparator treatment group. 16 factors were reported to be associated with a poor outcome, with longer duration of symptoms the most reported (&gt;4 months). Preliminary evidence suggests increased midfoot mobility may predict those who have a successful outcome to foot orthoses. Conclusions Current evidence can identify those with increased risk of a poor outcome, but methodological limitations make it difficult to predict the outcome after one specific treatment compared with another. Adequately designed randomised trials are needed to identify treatment effect modifiers.
Impact of the Addition of Rituximab to Initial CHOP Chemotherapy Compared with CHOP Alone in Patients with Relapsed Diffuse Large B-Cell Lymphoma Who Underwent Autologous Stem Cell Transplantation.
Authors: Yi-Bin Chen, Ephraim P. Hochberg, Yang Feng, Gabriela Motyckova, Donna Neuberg, Thomas R. Spitzer, David C. Fisher, Ann S. LaCasce
Journal: Blood (2007)
297. Sensitivity and Mechanisms of Resistance of Human Induced Pluripotent Stem Cells To the Inducible Caspase-9 Safety Switch
Authors: Shigeki Yagyu, Malcolm K. Brenner
Journal: Molecular Therapy (2015)

Introduction of inducible caspase-9 suicide gene (iC9) is one of the most appealing safety strategies for the cell therapy. iC9-mediated cell death is produced by direct activation of the pro-apoptotic molecule in the downstream portion of the intrinsic apoptotic pathway, so that potent and rapid killing is observed in the presence of the chemical inducer of dimerization (CID). To control the cell fate of human induced pluripotent stem cells (hiPSC) and minimize the possible unwanted effect of therapies using hiPSC, we produced hiPSC that expressed the iC9 safety system. In this system, over 99% of iC9-transduced hiPSC (iC9-iPSC) could be effectively eliminated in less than 24hrs after exposure to CID. There were, however, a small number of resistant cells that subsequently outgrew, and we have now investigated the mechanisms of resistance and devised approaches by which it may be overcome. We first purified a resistant population by culturing iC9-iPSC with CID. iC9-resistant iPSC were not killed even at a 30 fold higher dose of CID (% of live cells after CID exposure = 81.33±2.18%). iC9-and iC9-resistant iPSC had similar iC9 copy number. However, iC9 expression and induction of caspase-9/-3 activation was significantly lower in iC9-resistant iPSC than in iC9-iPSC. The CpG islands of the EF1α promoter sequence used as the iC9 transgene promoter, were more highly methylated in iC9-resistant iPSC, and the HDAC inhibitor, LBH589, could restore iC9 expression and partially enhance the CID sensitivity in iC9-resistant iPSC (% of live cells after LBH589+CID exposure; 45.25±3.4%). iC9 re-transduction in iC9-resistant iPSC could also restore the iC9 expression to similar levels as initially sensitive cells and greatly enhanced their sensitivity to killing by CID (% of live cells 24 hours after CID exposure = 24.16±2.33%). The sensitivity of the re-transduced cells remained lower even after increasing iC9 expression by re-transduction. In these cells, bcl-2 protein was highly expressed compared to the parental iPSC or iC9-iPSC. Moreover, the bcl-2 inhibitor, ABT-737, enhanced expression of activated caspase-9/-3, and augmented sensitivity to cytotoxicity produced by CID (% of live cells after ABT373+CID exposure; 18.31±0.03%). Bcl-2 family proteins regulate the intrinsic apoptotic pathway by blocking the mitochondrial disruption which triggers the activation of caspase-9 singling cascade. Because the caspase-9 signaling cascade also induces mitochondrial disruption through the cleavage of bcl-2 family protein, which thereby amplifies the intrinsic apoptotic pathway, our data suggest that both epigenetic silencing of iC9 transgene and overexpression of bcl-2 protein account for the resistance seen in a small proportion of iC9-iPSC to induction of apoptosis (Figure 1), and indicate means by which the high efficiency of killing mediated by this system can be further increased.
Genetic Characterization of Patients with Monoallelic and Biallelic CEBPA Mutations Using a Targeted Sequencing Approach Reveals Differences in the Spectrum of Cooperating Mutations
Authors: Nikola P Konstandin, Klaus H. Metzeler, Annika Dufour, Philipp A Greif, Tobias Herold, Bianka Ksienzyk, Stephanie Schneider, Wolfgang E Berdel, Thomas Büchner, Bernhard J. Woermann, Cristina Sauerland, Jan Braess, Wolfgang Hiddemann, Stefan K Bohlander, Karsten Spiekermann
Journal: Blood (2014)
Incidence, Risk Factors, Treatment and Outcome of Isolated Extramedullary Relapse after Allogeneic Stem Cell Transplantation for Acute Leukemia and Myelodysplastic Syndrome
Authors: Noga Shem-Tov, Francesco Saraceni, Ivetta Danylesko, Ronit Yerushalmi, Arnon Nagler, Avichai Shimoni
Journal: Blood (2015)
303. AAV Capsid Evolution for Enhanced Antibody Delivery To Human Muscle for Use in Next-Generation HIV Vaccines
Authors: Nicole K. Paulk, Greg W. Charville, Katja Pekrun, Katie Maguire, Thomas A. Rando, Mark A. Kay
Journal: Molecular Therapy (2015)

Our goal is to develop a recombinant adeno-associated virus (AAV) vector that is both resilient to neutralization by pre-existing human antibodies, and can efficiently transduce human muscle after systemic or intramuscular administration at levels sufficient to express therapeutic quantities of human monoclonal antibodies with broad-spectrum protection against HIV for use as a prophylactic vaccine and as a treatment for HIV-infected individuals. We hypothesized that capsid library screens in human skeletal muscle cells both in vitro and in vivo would be an ideal route to accomplish these goals. We utilized wild-type replicating AAV libraries of 10e5 variants via DNA shuffling of eleven different parental AAV capsids. Our libraries selectively replicate in human cells when co-administered with wild-type adenovirus, making chimeric humanized muscle mice and human muscle cell cultures excellent tools to allow for selection of capsids with tropism for human muscle cells. Two in vivo screens are ongoing in chimeric humanized muscle mice. These screens involve transplanting immunodeficient mice with pooled primary human muscle stem cells FACS-purified from skeletal muscle biopsies from five human donors. Human muscle progenitors fuse with those from the mouse and create chimeric myofibers expressing human muscle proteins for AAV selection. AAV capsid libraries are used to serially infect xenotransplanted mice and are then replicated with either Adenovirus-19b or 36. Two in vitro screens were performed in either primary human muscle stem cells isolated and purified from patient biopsies, or differentiated human myotubes. Completed screens were carried out for six rounds of replicating selection with Adenovirus-5 and the five most highly selected variants from each screen were sequenced and vectorized into EF1a-driven GFP-luciferase dual expression vectors. We are validating these 10 highly selected variants with comparisons to parental serotypes with some known muscle tropism (AAVs 1,6,8,9), as well as establishing neutralizing antibody levels against pooled human immunoglobulins. Vectors are being tested in humanized muscle mice and various human muscle cell lines (both healthy and diseased) by four methods of administration (intra-muscular, intra-arterial, intra-venous and intra-peritoneal) at a variety of doses for robust transgene expression. Best candidates will be used to package broadly neutralizing antibodies against HIV for further pre-clinical validation as a vaccine delivery agent. More generally, we hope to provide the muscle gene therapy community with a panel of optimized capsids with enhanced tropism for numerous muscle cell types with broad potential applications.
Polymorphism in the Promoter Region of the Hemeoxygenase I Gene of the Donor Influences Overall Survival and Graft Versus Host Disease.
Authors: Armin Gerbitz, Patrick Hillemanns, Christoph Schmid, Andrea Wilke, Rajshri Jayaraman, Hans-Jochem Kolb, Heike Bremm, Guenther Eissner, Ernst Holler
Journal: Blood (2006)
Bariatric Surgery for Autoimmunity?
Authors: Eleanor J. M. Rudge, Eric G. Sheu
Journal: JAMA Surgery (2016)

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Association between inflammatory markers, symptom burden, hypogonadism, and survival in cancer patients with cachexia
Authors: E. Del Fabbro, D. Hui, Z. Nooruddin, S. Dalal, G. Freer, L. Palmer, E. Bruera
Journal: Journal of Clinical Oncology (2009)

9594 Background: Cancer cachexia is characterized by muscle wasting, anorexia, and elevated inflammatory markers. Similarly, in patients without cancer, hypogonadism is associated with lower lean body mass, increased symptom burden and decreased survival. Hypogonadism in cancer cachexia could exacerbate symptom distress, facilitate a pro-inflammatory state and decrease survival. Currently, there are no guidelines for testosterone replacement therapy in cancer patients. We evaluated the relationship between hypogonadism, symptom severity, inflammation and survival in patients with cachexia. Methods: A retrospective chart review of 159 consecutive patients (61 females, 98 males) referred to a specialized cachexia clinic at a comprehensive cancer center. 98 patients (62%) had C-reactive protein (CRP) levels measured, and 68(69%) males had serum total testosterone evaluated. Testosterone levels were not evaluated in female patients. Symptoms were assessed by the Edmonton Symptom Assessment Scale (ESAS). Results: All patients reported weight loss of &gt;5% within the preceding 6 months; Median age was 62, CRP 26mg/L and in males median total testosterone186ng/dL (normal level≥240 ng/dL). Spearman correlation revealed higher CRP levels (r=0.57, p&lt;0.01) increased dyspnea (r=0.27, p&lt;0.05) and poorer sleep scores (r=0.29, p&lt;0.05) in males with low testosterone. In 46 males and females who underwent CRP testing within 30 days of their ESAS evaluation, pain (r=0.48, p&lt;0.01), fatigue (r=0.39, p&lt;0.01), poor appetite (r=0.49, p&lt;0.01), insomnia (r=0.42, p&lt;0.01), anxiety (r=0.29, p&lt;0.05), and dyspnea (r=0.31, p&lt;0.05) correlated with an elevated CRP. Survival of male patients with testosterone&lt;186 ng/dL was decreased compared to those with levels ≥ 186ng/dL (13 vs.62 weeks, p=0.004). Patients with CRP&gt;10 mg/L had decreased survival compared to those &lt;10 mg/L (30 vs. 66 weeks, p=0.017). Conclusions: Elevated C-RP levels in cancer cachexia are associated with poorer survival and increased symptom burden. Low testosterone is strongly associated with decreased survival in cachectic male patients and correlates inversely with CRP levels, dyspnea and insomnia. No significant financial relationships to disclose.
Abstract 1632: Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma
Authors: Anna Kock, Karin Larsson, Raouf Joan, Marina Korotkova, John-Inge Johnsen, Per-Johan Jakobsson, Per Kogner
Journal: Cancer Research (2015)

Abstract Background: Tumor promoting inflammation is important for Neuroblastoma development and progression. We have previously shown that the inflammatory prostaglandin E2 (PGE2) acts as an autocrine survival factor in NB and that high expression of microsomal prostaglandin E synthase-1 (mPGES-1), essential for PGE2 synthesis, is coupled to poor clinical outcome in high risk NB. We have also shown that mPGES-1 promotes growth and survival of several malignancies. In this study we investigate the impact of specific PGE2 targeting in NB by using a novel mPGES-1 inhibitor in vivo. Methods: The in vivo effect of the mPGES-1 inhibitor on tumor growth was carried out using the MYCN driven transgenic mouse model that spontaneously develops an aggressive form of neuroblastoma (tg TH-MYCN model). Protein and mRNA expression of mPGES-1 and the COX enzymes in the tumors was determined by immunohistochemistry (IHC) and RT-qPCR. Infiltration and polarization of macrophages in treated and nontreated tumors was assessed by IHC using the PAN-marker F4/80 and the M2 polarized macrophage marker CD206. The effect of mPGES-1 inhibition on angiogenesis was determined by IHC by using the endothelial marker CD31. Results: Expression of mPGES-1 and COX-1 could be detected in tumours from the tg TH-MYCN model. By treating the animals with the mPGES-1 inhibitor we could significantly delay the tumor growth with reduced tumor weights at sacrifice compared to tumors from untreated control animals. To study the effect of inflammation we analyzed macrophage abundance and polarization in the treated and untreated tumors. There was no diffrence in the total level of macrophage infiltration while a significant decrese of M2 polarized macrophages was seen in the treated tumors. Furthermore, mPGES-1 inhibition significantly reduced angiogenesis in the tumors. Conclusion: Our results demonstrate that specific PGE2 inhibition by targeting mPGES-1 is a way of reducing NB growth. Note: This abstract was not presented at the meeting. Citation Format: Anna Kock, Karin Larsson, Raouf Joan, Marina Korotkova, John-Inge Johnsen, Per-Johan Jakobsson, Per Kogner. Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma. [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 1632. doi:10.1158/1538-7445.AM2015-1632
PTH-006 Radiology reporting changes in the colorectal multidisciplinary team meeting: is patient management affected?
Authors: M T Lacey, P Bevis, R Hallifax, R Hopkins, N Borley, T Brooklyn, J Wheeler
Journal: Gut (2010)

<h3>Introduction</h3> The multidisciplinary team (MDT) is an established integral part of the National Cancer plan, its decisions forming the gold standard for cancer care. We investigated whether formally issued radiological reports were subsequently changed or added to at the colorectal MDT, and if this affected patient management. <h3>Methods</h3> We prospectively identified all patients with a new diagnosis of colorectal cancer over a 3-month period. Copies of the radiological report due to be discussed were attained, and compared to any modifications or additions at the MDT to identify any potential changes in management of the patient. <h3>Results</h3> A total of 105 patients (2:1 male to female ratio), with a median age of 65 years were reviewed. 16 of the 105 patients (15%) had their reports modified or added to. 13 patients (81%) of change patients had a change or modification that was considered major, impacting upon ultimate diagnosis and management. As a result three patients (23%) had their surgery cancelled and, two patients (15%) had their surgery delayed while awaiting further investigations. Two patients (15%) had a malignant finding changed to a benign and, three patients (23%) were changed to a curative resection having been previously considered as palliative. Two patients (15%) had the original curative procedure together with a distant plus another organ resection, and one patient (8%) had their surgery brought forward. 3 patients (19%) of change patients had a change or modification that was considered minor, having no impact upon their diagnosis or management. <h3>Conclusion</h3> The MDT identifies a significant minority (12%) of patients with new cancers whose management is changed significantly by review of radiology.
GRASPALL 2005.01 Clinical Study: L-Asparaginase Loaded into Red Blood Cells Is Effective at Depleting Serum Asparagine in Children and Adults with Relapsed Acute Lymphoblastic Leukaemia (ALL)
Authors: Yves Bertrand, Xavier Thomas, Andre Baruchel, Françoise Mazingue, Anne Auvrignon, Selim Corm, Herve Dombret, Patrice Chevallier, Claire Galambrun, Françoise Huguet, Faezeh Legrand, Françoise Mechinaud, Norbert Vey, Sylvie Chabaud, Florence Noel Baron, Irène Philip, David Liens, Yann Godfrin
Journal: Blood (2008)