tbuckley/cabot-search huggingface dataset:
717. Revising the Common Rule: Changes to the Federal Policy Protecting Human Subjects
Authors: Bambi Grilley
Journal: Molecular Therapy (2016)

The protection of human subjects involved in research in the United States (U.S.) is based on the Belmont Report. The current regulations governing these protections were published in 1991 and are followed by 18 federal agencies. These regulations are referred to as the Common Rule. In July of 2011 the U.S. Department of Health and Human Services (HHS) issued an Advance Notice of Proposed Rulemaking (ANPRM) asking for public comment on proposed changes to the Common Rule. The comment period for the ANPRM ended in October 2011. In September 2015 HHS released a Notice of Proposed Rulemaking (NPRM) that included clarifications and modifications based on the feedback they received from the ANPRM. The NPRM also asked for public comment on the now modified proposed changes to the Common Rule. The comment period for the NPRM ended on January 2016. The NPRM document is quite long and detailed however a summary of the changes can be categorized into three major categories. The first category is increasing subject ability and opportunity to make informed decisions through modifications of requirements for informed consent documents. The second category is reducing the potential for harm and increasing justice for all subjects by increasing requirements for privacy protections inclusive of biospecimen research, expanding coverage of the protections to be inclusive of all clinical trials regardless of funding source, and expanding requirements for compliance with the Common Rule to all Institutional Review Boards (IRBs) inclusive of those not affiliated with an assurance holding institution. The third major category is facilitating current/evolving research that offers promising approaches by reducing ambiguity in the interpretation of the regulations, increasing efficiencies in the performance of the review system most specifically in the area of continuing review requirements and reducing burdens on researchers that do not appear to provide commensurate protections to human subjects (inclusive of re-defining exempt research categories and proposing a new research category identified as excluded research). Implementation of the Final Rule will be one year following publication allowing for voluntary application of provisions that provide regulatory flexibility to occur as early as 90 days after publication while other categories allow for implementation to occur as long as 3 years after publication. Many of the proposed changes relate to the use of biospecimens which will have significant impact on cell and gene therapy researchers. The regulatory community anticipates that the Final Rule will be released in 2016. If the Final Rule is released prior to the ASGCT meeting this presentation will focus on the Final Rule. If the Final Rule is not release prior to the ASGCT meeting this presentation will provide more in-depth information regarding the NPRM.
Dietary modification to reduce cardiovascular risk factors in patients receiving androgen-deprivation therapy for prostate cancer.
Authors: A. E. Mega, M. Flynn, A. M. Plette, M. Jean, H. Hue, H. Safran
Journal: Journal of Clinical Oncology (2011)

e15053 Background: Androgen-deprivation therapy (ADT) is associated with the metabolic syndrome and cardiovascular disease (unfavorable lipid profile, obesity and insulin resistance). The Mediterrean Diet (MedD), a diet high in olive oil, fruits, vegetables, nuts and whole grains, may reduce the risk of the metabolic syndrome. An 8-week MedD program was administered to assess the feasibility of intensive dietary modification in patients with prostate cancer on ADT. Methods: Men receiving androgen therapy for prostate cancer were eligible. Only men receiving ADT as adjuvant therapy, for biochemical relapse or for stable metastatic disease were eligible. Patients were instructed to increase daily consumption of extra virgin olive oil to 90mls and > 4 servings of vegetables. Poultry and seafood were limited to 8oz a day. Dietary records were maintained by patients and reviewed during week 4 and 8. Anthropometric measures and blood work was performed pre and post diet. Weight-loss goal was 5% of pre-program weight. Outcome Measures: percent weight loss (PWL), waist circumference (WC), HDL, LDL, insulin levels, fasting triglyceride level (FTG) and blood glucose (FBG). Results: 20 patients were enrolled of which 16 completed the study (2 diet noncompliant, 2 consented but did not start). No patient had symptomatic disease progression while on study. The median age was 70.9 years. PWL was 5.9%. Treatment results are summarized below (Table). Conclusions: An 8-week MedD program is associated with a reduction in central obesity and triglycerides. Increased emphasis should be placed on dietary modification to reduce cardiovascular mortality in men receiving ADT for prostate cancer. This pilot trial suggests that an eight week MedD may be able to modify dyslipidemia and abdominal obesity. Further evaluation is indicated. Baseline Post diet P value BMI (kg/m2) 32.5+/-4.2 30.5+/-3.6 <0.01 Waist (cm) 106.7+/-9.4 102.4+/-8.9 <0.01 LDL (mg/dl) 113+/-19 113+/-26 0.94 HDL (mg/dl) 46+/-11 44+/-9 0.25 FTG (mg/dl) 109+/-46 86+/-38 <0.01 Insulin (uIU/ml) 11.8+/-7.5 9.9+/-9.2 0.12 FBS (mg/dl) 108+/-11 105+/-7 0.12
Diagnostic Utility of Flow Cytometry in Myelodysplastic Syndrome: A Retrospective Validation From a Single Centre.
Authors: Pervin Topcuoglu, Klara Dalva, Sule Mine Bakanay, Sinem Civriz Bozdag, Onder Arslan, Muhit Ozcan, Mutlu Arat, Meral Beksac, Gunhan Gurman
Journal: Blood (2009)
Interleukin 6–dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis
Authors: Tali Lanton, Anat Shriki, Yael Nechemia‐Arbely, Rinat Abramovitch, Orr Levkovitch, Revital Adar, Nofar Rosenberg, Mor Paldor, Daniel Goldenberg, Amir Sonnenblick, Amnon Peled, Stefan Rose‐John, Eithan Galun, Jonathan H. Axelrod
Journal: Hepatology (2016)

Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For patients with liver cancer, surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long‐term survival of these patients. We have shown that partial hepatectomy in multidrug resistance 2 knockout (Mdr2 –/– ) mice, a model of chronic inflammation‐associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the postsurgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2 –/– mice by perioperative pharmacological inhibition of interleukin‐6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following partial hepatectomy without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2 –/– mice contain hepatocytes with a notable persistent DNA damage response (γH2AX, 53BP1) due to chronic inflammation. We show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei, a marker of genomic instability, which is suppressed by IL6 blockade. Conclusion : Our findings indicate that genomic instability derived during the IL6‐mediated liver regenerative response within a milieu of chronic inflammation links partial hepatectomy to accelerated hepatocarcinogenesis; this suggests a new therapeutic approach through the usage of an anti‐IL6 treatment to extend the tumor‐free survival of patients undergoing surgical resection. (H epatology 2017;65:1600‐1611)
Abstract LB-251: Histone deacetylase inhibition for the treatment of epithelioid sarcoma; novel cross talk between epigenetic components
Authors: Gonzalo Lopez, Yechun Song, Dennis Ruder, Chad Creighton Creighton, Svetlana Bolshakov, Xiaoli Zhang, Dina Lev, Raphael Pollock
Journal: Cancer Research (2015)

Abstract Objective Enhanced knowledge of epithelioid sarcoma (ES) molecular determinants will hopefully aid the development of urgently needed targeted therapies. The hallmark loss of INI1 causes a disruption in epigenetics, potentially contributing to the development of the disease. Recently, we have demonstrated that HDAC inhibitors (HDACi) to have efficacious value for the treatment various genetically complex sarcomas. Here, we aim to evaluate the potential therapeutic efficacy of HDACi in ES. Methods Three ES cell lines were used for this study: Epi-544, HS-ES, VAESBJ. MTS and clonogenic assays were utilized to evaluate the effect of HDACi on cell line growth. Cell cycle FACS and annexin V PI/FACS analysis with WB for cleaved caspase 3 were used to determine the effects of HDACi on cell cycle and apoptosis, respectively. In vivo growth effects of HDACi were evaluated using SCID mouse ES xenograft models. An Illumina gene array was used to evaluate HDACi-induced gene change. Results HDACi inhibited ES cell growth and colony formation. HDACi induced G2 cell cycle arrest and enhanced apoptosis in all ES cell lines tested. Similarly, HDACi abrogated ES xenograft growth and increased apoptosis in vivo. Due to the HDACi mechanisms of function, one of the major consequences of this therapy is gene expression modulation. Using an Illumina gene array, we sought to identify genes responsible for the in vitro and in vivo anti-ES effects observed. Array analysis showed Survivin be significantly down-regulated in response to HDACi treatment. HDACi-induced decrease of Survivin was confirmed via WB. For enrichment analysis of our genes set with published annotated gene signatures, the Molecular Signatures Database (MSigDB) was used. MSigDB analysis identified a curated gene set of regulated genes after EZH2 knockdown (KD) with significant commonality of our gene array. We demonstrated HDACi-induced decrease of EZH2. EZH2 KD resulted in reduced cell growth and increased apoptosis in VAESBJ cells. Conclusion HDACs play a role in the progression of ES, where HDACi abrogate ES cell growth and enhance apoptosis in vitro and in vivo. Gene array analysis revealed various genes modulated by HDACi that may contribute to the progression of the disease. Anti-ES effects may be in part through the HDACi-induced repression of EZH2. Citation Format: Gonzalo Lopez, Yechun Song, Dennis Ruder, Chad Creighton Creighton, Svetlana Bolshakov, Xiaoli Zhang, Dina Lev, Raphael Pollock. Histone deacetylase inhibition for the treatment of epithelioid sarcoma; novel cross talk between epigenetic components. [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 LB-251. doi:10.1158/1538-7445.AM2015-LB-251
Higher Vascular Endothelial Growth Factor (VEGF) and Endothelial Progenitor Cells (EPCs) in Multiple Myeloma (MM) Patients (pts) as a Reflection of Their Governing Role in Pathological Angiogenesis: Comparison of VEGF and EPC Levels Between Healthy Donors (HD), MGUS and MM Pts and Correlation Analysis with MM Activity
Authors: Josefina Udi, Martina Kleber, Dagmar Wider, Ralph Wäsch, Monika Engelhardt
Journal: Blood (2008)
119. HIV-1 Proviral DNA Excision and Deactivation Using a CRISPR/Cas9 “Nickase” Targeted to the 5’ and 3’ LTR
Authors: Tristan Scott, Sheena Saayman, Daniel Lazar, Patrick Arbuthnot, Isidor Rigoutsos, Kevin Morris, Fatah Kashanchi, Marco Weinberg
Journal: Molecular Therapy (2015)

Permanent integration of the HIV-1 provirus in the host genome ensures a persistent supply of latently infected HIV cells capable of reactivation. This latent reservoir is recalcitrant to antiretroviral therapy (ART) making lifelong treatment the only option for patients. Therapies aimed at targeting the latent virus offer a promising approach to a "functional cure" of HIV/AIDS. Several gene editing technologies, including ZFNs, TALENs, Tre-recombinases and RNA-guided CRISPR/Cas9 tools have been used to disrupt the HIV-1 genome and suppress viral gene expression and replication in latently-infected cells. While CRISPR/Cas9 represents a powerful and facile DNA editing technology, toxicities associated with the Cas9 nuclease activity remains a concern. Here we explore the use of a "nickase" Cas9 (nCas9), which has a mutated RuvC I catalytic domain, and requires the combination of two adjacent small guide RNAs (sgRNAs) for on-target editing and specificity. We initially identified 9 sgRNA sequences targeted to conserved sites within the HIV TAR element, found on both the 5' and 3' LTRs. Using integrated and episomal LTR-driven luciferase reporters, we identified functional sgRNA "nickase pairs" capable of inducing an 80% reduction in gene expression, as well as excision of the proviral DNA. Using HIV-1 latency models, plasmids expressing nCas9 and the sgRNA pairs were nucleofected into HIV-1 integrated cell lines J1.1, CHME5 and U1 and treated with the histone deacetylase inhibitor trichostatin A (TSA) to activate infection. All treated cells showed significant reduction (up to 80% for J1.1) in infectious viral output. Cleavage was further verified using ChIP assays to detect DNA damage response proteins recruited to the targeted locus in all cell lines. Lastly, using a custom algorithm for detecting off-target cleavage sites (https://cm.jefferson.edu/Off-Spotter/), we identified 8 sites for each sgRNA within the "nickase pair". No off-target editing was observed at these loci following high throughput NGS analysis. In conclusion, we showed that CRISPR/Cas technology represents a powerful tool at eradicating and/or deactivating the integrated HIV-1 provirus and that using the Cas9 nickase is just as effective as wild-type Cas9 but with the added advantage of providing a significant additional layer of safety for future in vivo applications.
Abstract 193: Epigenetic regulation of Notch1 signaling-driven melanoma progression
Authors: Ling Yin, Qinghua Huang, Alan S. Livingstone, Omaida C. Velazquez, Zhao-Jun Liu
Journal: Cancer Research (2015)

Abstract Objectives. Aberrant Notch signaling promotes melanoma progression, yet the underlying molecular mechanism remains largely unknown. We hypothesized a potential involvement of epigenetic mechanism in this process and sought to identify Notch-regulated miRNAs and their functional targets. Methods. Notch-regulated miRNAs were identified by examining miRNA profiles in response to Notch activation/inhibition in human melanoma cells using RT2-miRNAArray. The role of specific miRNA in mediating the oncogenic effect of the Notch signaling was studied by testing whether alteration of miRNA expression could reverse the Notch's effects on melanoma cell growth, survival and colony-formation in vitro, and lung metastasis in vivo. The targets of the Notch-regulated miRNA were identified by searching miRNA target database and validated by immunoblot. The roles of miRNA targets in mediating the Notch's oncogenic effects were further assessed by in vitro colony-formation and in vivo lung metastasis assays. Results. Notch activation down-regulated mi143 in melanoma cells. Reconstituted expression of mi143 antagonized Notch1's oncogenic effect. The anti-oncogenic effect of mi143 is mediated by inhibiting Notch1-induced expression of FGF-1, uPA and uPAR since expression of these targets was up-regulated by the Notch1 activation while down-regulated by reconstituted overexpression of mi143. Supplementation of exogenous FGF-1 or reconstituted expression of uPA/uPAR, but not uPA alone, reversed the suppressive effect of mir143 on Notch-enhanced melanoma cells colony formation in soft-agar or lung metastasis in SCID mice. Conclusions. Notch activation up-regulates expression of FGF-1, uPA and uPAR through down-regulating mi143 expression in melanoma cells. mi143 is responsible for mediating aberrant Notch signaling-driven melanoma progression. The effect of down-regulated mi143 is transmitted through elevated FGF-1 and enhanced uPA-uPAR signaling activity, but not enzyme activity of uPA. This study unveils novel Notch1/mi143/FGF-1 and Notch1/mi143/uPA-uPAR cascades and uncovers an epigenetic mechanism underlying the oncogenic effect of Notch signaling, and provides potential novel targets for melanoma prognosis and therapy. Note: This abstract was not presented at the meeting. Citation Format: Ling Yin, Qinghua Huang, Alan S. Livingstone, Omaida C. Velazquez, Zhao-Jun Liu. Epigenetic regulation of Notch1 signaling-driven melanoma progression. [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 193. doi:10.1158/1538-7445.AM2015-193
The Phenotypic Spectrum of Pyruvate Kinase Deficiency (PKD) from the PKD Natural History Study (NHS): Description of Four Severity Groups By Anemia Status
Authors: Rachael F. Grace, D Holmes Morton, Wilma Barcellini, Stefan W. Eber, Jenny M Depsotovic, Christine M. Knoll, Hassan M. Yaish, Peter E. Newburger, Jennifer Rothman, Alexis A. Thompson, Yaddanapudi Ravindranath, Joachim Kunz, Eduard J van Beers, Marcin W Wlodarski, Kerri A Nottage, Heng Wang, Mukta Sharma, Melissa J. Rose, Yves D. Pastore, Patricia J. Giardina, Melissa Rhodes, Kevin Kuo, Vicky R. Breakey, Ellis J. Neufeld, Dongjing Guo, Wendy B. London, Jill Falcone, Bertil Glader
Journal: Blood (2015)
PTH-033 Detection of duodeno-gastric reflux during routine 99mTc-hida scintigraphy
Authors: L I Sonoda, M Y Halim, S Middleton, K K Balan
Journal: Gut (2010)

<h3>Introduction</h3> Duodeno-gastric reflux (DGR) is an incidental finding on 99mTc-HIDA studies but its detection often yields useful clinical information. Present study was carried out to determine the rate of detection as well as incidence of DGR in patients undergoing routine HIDA imaging over a 5-year-period. <h3>Methods</h3> One hundred and eighty-three sequential patients (52 males, 131 females, mean age 46 years old) who underwent 99mTc-HIDA cholescintigraphy over a 5-year-period between 2004 and 2008 have been retrospectively reviewed. Age, sex, previous surgery, clinical indications for the study, presence or not of DGR and clinical reports were subjected to analysis. <h3>Results</h3> Biliary dyskinesia (n=135; 74%), post-surgical symptoms (n=33; 18%) and sphincter of Oddi dysfunction (n=15; 8%) were the main indications for the study. 33/183 (18%) patients had DGR of which 21 (64%) were present in 117 patients with otherwise normal studies while 12 (36%) were seen in 66 patients with abnormal results (p=0.87). All except one case of DGR was detected and mentioned in the original clinical report. 25/132 (19%) and 8/51(18%) patients, respectively, with normal and abnormal biliary tract anatomy were found to have DGR (p=0.76). Occurrence of DGR had no significant relationship with age, sex or gall bladder ejection fraction. <h3>Conclusion</h3> DGR is an easily detected common finding on routine cholescintigraphy and may be the cause of presenting symptoms in patients who may have an otherwise normal HIDA study. The occurrence of DGR does not appear to have any significant relationship with age and sex of patients, biliary tract anatomy, or gall bladder function.
Long-Term In Vivo Studies in Mice Unexpectedly Reveal That Prolonged Growth Hormone (GH) and Insulin/Insulin-Like Growth Factor-1 (IGF-1) Signaling Have a Negative Effect on Normal Bone Marrow Hematopoiesis – Implications for GH-Based “rejuvenation” Therapies,
Authors: Janina Ratajczak, Rui Liu, Magda Kucia, Andrzej Bartke, Mariusz Z Ratajczak
Journal: Blood (2011)
CC-002 Not just another bleeding ulcer
Authors: J A Evans, R Goel, J Tibble
Journal: Gut (2010)

<h3>Introduction</h3> Isolated pancreatic tuberculosis (TB) is exceptionally rare, but increasing numbers of cases are being reported. This is attributed to the growing TB and human immunodeficiency virus (HIV) pandemic. <h3>Methods</h3> We report a case of a 39-year-old male who presented with acute upper gastrointestinal bleeding secondary to pancreatic TB. Oesophogastroduodenoscopy (OGD) was undertaken showing a duodenal ulcer with duodenitis. He was discharged on regular proton pump inhibitor for 6 weeks. 3 months later he was referred by his GP for further investigation of recurrent abdominal pain and deranged liver function tests. Ultrasound and CT showed a pancreatic mass and a diagnostic laparoscopy with omental biopsy for suspected pancreatic carcinoma was performed. <h3>Results</h3> Omental biopsies revealed widespread granulomatous inflammation and staining for acid fast bacilli was positive. There was no pulmonary involvement and HIV testing was negative. CT scan and follow-up OGD after 12 months of anti-tuberculous treatment showed complete resolution. The range of differential diagnoses, histopathological findings, investigative difficulties and treatment options are discussed. <h3>Conclusion</h3> Pancreatic TB is difficult to diagnose due to the way it mimics a range of other conditions. Pancreatic TB should be considered as a differential diagnoses for a pancreatic mass especially in patients who have travelled to or from areas where the disease is endemic. With appropriate treatment pancreatic TB shows excellent response rates and can obviate unnecessary surgery.