tbuckley/cabot-search huggingface dataset:
Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine
Authors: Ramesh Subbiah, Robert E. Guldberg
Journal: Advanced Healthcare Materials (2018)

Abstract Growth factors (GFs) are signaling molecules that direct cell development by providing biochemical cues for stem cell proliferation, migration, and differentiation. GFs play a key role in tissue regeneration, but one major limitation of GF‐based therapies is dosage‐related adverse effects. Additionally, the clinical applications and efficacy of GFs are significantly affected by the efficiency of delivery systems and other pharmacokinetic factors. Hence, it is crucial to design delivery systems that provide optimal activity, stability, and tunable delivery for GFs. Understanding the physicochemical properties of the GFs and the biomaterials utilized for the development of biomimetic GF delivery systems is critical for GF‐based regeneration. Many different delivery systems have been developed to achieve tunable delivery kinetics for single or multiple GFs. The identification of ideal biomaterials with tunable properties for spatiotemporal delivery of GFs is still challenging. This review characterizes the types, properties, and functions of GFs, the materials science of widely used biomaterials, and various GF loading strategies to comprehensively summarize the current delivery systems for tunable spatiotemporal delivery of GFs aimed for tissue regeneration applications. This review concludes by discussing fundamental design principles for GF delivery vehicles based on the interactive physicochemical properties of the proteins and biomaterials.
TMOD-28. MYC OVEREXPRESSION DRIVES MEDULLOBLASTOMA FROM HUMAN NEUROEPITHELIAL STEM CELLS
Authors: Sonja Hutter, Holger Weishaupt, Gabriela Rosén, Fredrik Swartling
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children. Based on molecular genetic profiling, this disease can be classified into four major subgroups which display distinct clinical features. Group 3 MBs are associated with overexpression or amplification of the MYC oncogene and rarely show any mutations in the tumor suppressor protein p53. Patients with MYC-driven MB have a particularly high risk of recurrence and are associated with extremely poor prognosis. Thus, modeling MYC-driven MB is critical for the development and testing of potential new treatment approaches for these high-risk MBs. Here we show the first human MB model developed from human hindbrain neuroepithelial stem (NES) cells and induced pluripotent stem cell-derived NES (iPS-NES) by lentiviral overexpression of wild-type MYC. Following orthotopic transplantation into immunodeficient mice these embryonic cells generate aggressive brain tumors with high penetrance in the absence of p53 mutations. The MYC-driven tumors are comprised of poorly differentiated cells with high expression of the proliferation marker Ki-67. Tumors also express early neuronal lineage marker Tuj-1 (neuron-specific class 3 beta tubulin) and the transcription factor OTX2. All these features closely mimic those of human Group 3 MB. The establishment of these human MYC-driven MB animal models will facilitate the functional study of MB biology and testing of potential therapies.
Loss of Gene Body Methylation in<i>Eutrema salsugineum</i>Is Associated with Reduced Gene Expression
Authors: Aline Muyle, Brandon S Gaut
Journal: Molecular Biology and Evolution (2018)

Gene body methylation (gbM) is typically characterized by DNA methylation in the CG context within coding regions and is associated with constitutive genes that have moderate to high expression levels. A recent study discovered the loss of gbM in two plant species (Eutrema salsugineum and Conringia planisiliqua), illustrating that gbM is not necessary for survival and reproduction. The same paper stated there was no detectable effect of gbM loss on gene expression (GE). Here, we reanalyzed the GE data and accounted for experimental variability in expression level estimates. We show that the loss of gbM in E. salsugineum is associated with a small but highly significant decrease in GE relative to the closely related species Arabidospis thaliana. Our results are consistent with various evolutionary analyses that suggest gbM has a function, perhaps as a homeostatic effect on GE.
Abstract 15660: Clopidogrel Reloading for Acute Myocardial Infarction Patients Already on Clopidogrel Therapy: Insights From ACTION Registry - Get With the Guidelines
Authors: Jacob A Doll, Shuang Li, Karen Chiswell, Mikhail Kosiborod, Benjamin M Scirica, Matthew T Roe, Wang Y Tracy
Journal: Circulation (2015)

Introduction: Guidelines recommend an early loading dose of a P2Y 12 receptor inhibitor for STEMI and NSTEMI patients, yet whether a loading dose is needed for patients already on clopidogrel therapy is unclear. Methods: We examined STEMI and NSTEMI patients on clopidogrel therapy on admission and without contraindications to cardiac catheterization in the ACTION Registry GWTG from 2009 to 2014. We used inverse probability weighted propensity adjustment to compare in-hospital mortality and major bleeding risks between patients reloaded in the first 24 hours with 300-600mg of clopidogrel vs. those continued on a maintenance (&lt;300 mg) dose without reloading. Results: Of 56,327 patients already on clopidogrel, 19,513 (35%) received a loading dose of clopidogrel within the first 24 hours of admission. Patients who were reloaded were younger (median 65 vs. 68 years), less likely to be female (33% vs. 38%) and to have cardiovascular risk factors such as diabetes, prior MI, and prior coronary revascularization. STEMI patients already on clopidogrel therapy were more likely to receive a loading dose than NSTEMI patients (76% vs. 26%, p&lt;0.001). Among STEMI patients, clopidogrel reloading was associated with lower unadjusted and adjusted risks of in-hospital mortality compared with those continued on clopidogrel without reloading, however no significant mortality difference was observed among NSTEMI patients (Table). Risk of major bleeding was not significantly different between patients with and without clopidogrel reloading regardless of MI type. Conclusion: Despite limited supporting evidence, clopidogrel reloading occurs frequently among patients who present with MI already on clopidogrel therapy, particularly among STEMI patients. We did not observe increased bleeding risk with clopidogrel reloading. The finding of lower mortality associated with clopidogrel reloading among STEMI patients warrants further investigation.
ATIM-42. SAFETY AND EFFICACY OF AUTOLOGOUS DENDRITIC CELLS/TUMOR CELL ANTIGEN ADJUVANT THERAPY OF GLIOBLASTOMA MULTIFORME: RESULTS OF 59 CASES
Authors: Yin-Cheng Huang, Chen-Nen Chang, Kuo-Chen Wei, Han-Chung Lee, Chun-Chung Chen, Der-Yan Cho, Wen-Kuang Yang
Journal: Neuro-Oncology (2018)

In our translational research, an immunotherapeutic, ADCTA-G, has been developed to emphasize autologous tumor antigens, DC antigen processing/presentation, enhanced tumor immunogenicity and CTL induction. Two clinical trials, Phase I/II [2003-2005Taiwan DOH/MA 0910072504] and phase II [2005–2016 NIH NCT02772094], “Dendritic Cell(DC)-Based Tumor Vaccine Adjuvant Immunotherapy of Human Glioblastoma Multiforme”, respectively enrolled 17 and 42 WHO Grade-IV glioblastomas. Every patient received peripheral blood apheresis for PBMNCs. Monocytes were used for derivation of 3-7x108 phagocytic dendritic cells (iDC). Autologous glioma cells grown out of surgical tumor specimen were irradiated and co-cultivated 1 to 2:1 with iDC to make a ADCTA-G lot. After surgical tumor de-bulking, 10 vaccinations were given, each with 2-5x107 mature DC from the ADCTA lot, in a [4x biweekly and 6x monthly] scheduled s.c. injection in both axillar regions. The follow-up period has been 15 years. Primary endpoint is the overall survival (OS); phenotypes of tumor infiltrating T cells and tumor IDH mutation were also analyzed for long-term survivors. The ADCTA-G inoculations were tolerated well, and curtailed the grade-3/4 lymphopenia adverse effect of the temozolomide CCRT. The median OS is 22.9 months for the total 59 grade IV patients in the two trials. The median OS is 21.8 months for the 44 newly diagnosed patients and 28.1 months for the 15 recurrent patients; the difference is insignificant statistically. In this study, vaccinations were initiated early in the recurrent GBM patients while the newly diagnosed GBM patients had to wait till after external radiation therapy, leading to a comparable OS benefit of the ADCTA vaccination. Also, we demonstrated in vitro the earlier vaccinations in the recurrent decrease CD133+ tumor stem-like cells. In addition, the CD8(+) cells were susceptible to ionizing radiation. A phase 3 open-labelled randomized study will be initiated to improve the survival of this aggressive malignancy.
Making doctors better: change doctors’ beliefs rather than provide special services
Authors: Ian Aston, Harj Kaul
Journal: BMJ (2018)

The BMJ ’s editorial on doctors’ wellbeing raises some very important points; doctors are under many pressures, as outlined in the article, and the results are evidenced by increased morbidity in the profession.1

Systemic solutions are important. If the working environment, procedures, and processes are causing illness, then changing and adjusting them is the only …
TMIC-44. ASTROCYTE SENESCENCE: A MODEL FOR AGE AND SEX EFFECTS ON GLIOBLASTOMA INCIDENCE
Authors: Cameron Hill, Gina Rhee, Joshua Rubin, Lauren Broestl, Jasmin Sponagel
Journal: Neuro-Oncology (2018)

Primary brain tumor incidence rates rise more rapidly in males than females with increasing age. Both pre-neoplastic cells and stromal elements contribute to age-related increases in cancer, and cellular senescence plays a role in the transformation of pre-neoplastic cells. While senescence prevents the proliferation of damaged cells, senescent cells produce senescence-associated secretory phenotypes (SASP) which contribute to the tumor microenvironment. Certain SASP factors favor tumor suppression by inducing senescence in neighboring cells or recruiting immune cells for tumor clearance, while other factors increase tumor proliferation, resistance and relapse. Studies have demonstrated the role of senescence in the growth of solid tumors in various tissues including the liver, pancreas, and prostate. However, no studies have investigated how senescence in resident brain cells influences age-dependent increases in brain tumors. Moreover, there are no data in any tissues about sex differences in cellular senescence and its effect on age-dependent cancer rates. In the brain, astrocytes are the most abundant resident cell type with critical functions in brain structure, physiology, and homeostasis. Thus, we investigated sex differences in astrocyte senescence and whether these differences contribute to the sex disparity in brain tumor rates, specifically glioblastoma which has a male to female ratio of 1.6. Using β-galactosidase staining, we found that murine female astrocytes undergo senescence more readily after oxidative stress than their male counterparts. Furthermore, in vitro studies showed that murine GBM cells cultured in female astrocyte SASP-conditioned media show a different pattern of growth as compared to those cultured in male astrocyte SASP-conditioned media. These results indicate that there are sex differences in astrocyte senescence that influence tumor proliferation. Further investigation into the molecular mechanisms involved in male and female senescent astrocytes will allow us to better understand age-dependent brain tumor growth, which may reveal novel therapeutic targets for treatment.
CBMT-47. THE ROLE OF PHOSPHOFRUCTOKINASE-1 IN GLIOBLASTOMA MAINTENANCE AND MOTILITY
Authors: Kamilla Jensen, Rikke Rasmussen, Kristoffer Vitting-Seerup, Irina Gromova, Pavel Gromov, Jane Skjøth-Rasmussen, Jeanette K Petersen, Bjarne W Kristensen, Jeremy N Rich, Petra Hamerlik
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) remains one of the most lethal tumors and is associated with a median survival of only approx. 15 months despite aggressive radio-chemo-therapy. One distinct challenge in GBM management includes diffuse location of the tumor within the brain and migration of cancerous cells into the healthy surrounding tissue preventing complete surgical removal and promoting recurrence. A subpopulation within the tumor mass, the so-called stem cells (or glioma initiating cells, GICs) are further complicating treatment strategies as this pool of cells is more invasive and is known to possess resistance to traditional therapy. It is commonly known that cancer cells utilize glucose as their main energy source, a phenomenon known as the Warburg effect. Phosphofructokinase-1 (PFK-1) is one of two rate-limiting enzymes in glycolysis and presents a potential critical check point for these glucose “addictive” cells. Additional to its glycolytic role we here propose a regulatory role for PFK-1 in motility in GICs. To elucidate the role of PFK-1 in GBM, we abrogated its function using shRNA-mediated knockdown or chemical inhibition. Next, we evaluated the cellular responses utilizing a broad range of in vitro assays including cell viability, apoptosis, cytoskeleton assembly, migration and invasion assay. Depletion of PFK-1 in GICs led to decreased viability and increased rates of apoptosis. Furthermore, impaired function of PFK-1 affected cytoskeleton assembly and decreased migration and invasion capacity, a phenotype we were able to mimic with a chemical PFK-1 inhibitor. PFK-1-regulated motility was found to be through translational regulation of KIF11. CONCLUSION: PFK-1 regulates GBM stem cell motility and invasion through the regulation of KIF11, a motor protein belonging to the kinesin-like protein family. The novel role of PFK-1 identified in our studies, together with successful therapeutic targeting in vitro and in vivo, expands our understanding of GBM maintenance and cell motility.
Abstract 11877: Beta-blocker Dose Stratifies Both Mortality Risk and Circulating Procollagen Levels In African-Americans With Heart Failure
Authors: Julio D Duarte, Meghan J Arwood, Ina Liko, Ibrahim Mansour, Mayank Kansal, Thomas Stamos, Larisa H Cavallari, Ankit A Desai
Journal: Circulation (2016)

Introduction: While African Americans (AAs) have the highest prevalence of heart failure (HF) and HF mortality, insufficient data exists regarding the impact of HF medication on mortality in AAs. This study aimed to identify medication use practices associated with survival in a predominantly AA HF population. Methods: HF patients were prospectively recruited from, and followed within, the University of Illinois Health System from 11/2001 to 11/2015, when vital status was determined. Data were extracted from electronic health records and Social Security Death Index. Beta-blocker (BB), ACE-I, and ARB doses were categorized as high, medium, or low based on published HF trials. Associations between dose and all-cause mortality were assessed using a Cox proportional hazard model, adjusting for enrollment age, sex, race, ischemic or non-ischemic etiology, NYHA functional class, and concomitant HF medication use. Using linear regression (adjusted for the same covariates), doses were also compared with plasma procollagen N-terminal peptide type III (PIIINP) levels, a previously shown marker for cardiac fibrosis. Results: In total, 352 patients (75% AA, 50% female, 63% HFrEF: LVEF &lt; 45%) consented to participate, with 84 dying by the end of data recording. Of those, 95% used BBs, 90% ACE-I/ARBs, and 19% ARAs. ACE-I/ARB dose was not associated with mortality (HR: 0.86, 95% CI: 0.62-1.17, P = 0.33). In contrast, increased BB dose was associated with reduced risk of death (HR: 0.64, 95% CI: 0.47-0.86, P = 0.003; Figure 1). This effect remained consistent when stratified by HFrEF or HFpEF. Higher BB (but not ACE/ARB) dose was also associated with lower circulating levels of PIIINP (N = 149 patients, P = 0.05), which still trended after further adjustment for BP and HR. Conclusions: These findings suggest that aggressive titration of BB dose, unlike ACE-I/ARB dose, may confer a mortality benefit in AA patients with HFrEF or HFpEF which may be mediated through decreased cardiac fibrosis.
Dialysis for Patients With End-stage Renal Disease Who Are Homeless
Authors: Tessa K. Novick, Crystal A. Gadegbeku, Deidra C. Crews
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
PDTM-34. TARGETING H3.3G34R/V RE-WIRING OF THE EPIGENOME IN PAEDIATRIC GLIOBLASTOMA OF CHILDREN AND YOUNG ADULTS
Authors: Lynn Bjerke, Alan Mackay, Diana Carvalho, Helen Pemberton, Valeria Molinari, Maria Vinci, Fernando Carceller, Lynley Marshall, Andrew Moore, Angel Montero Carcaboso, Chris Lord, Darren Hargrave, Chris Jones
Journal: Neuro-Oncology (2018)

Around 15% of cerebral hemispheric glioblastomas (GBM) of children and young adults harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. These tumours have a peak incidence in late adolescence but are found up to 30yrs of age, and have conflicting data as to their prognosis compared to histone wild-type cases. As little is known about its role in tumorigenesis, we sought to explore the underlying biology of H3.3G34R/V mutant GBM and identify novel avenues for therapeutic intervention through genomic, epigenomic and drug screening approaches in primary-patient-derived cultures. In combined retrospective and prospective cohorts of pHGG samples, H3.3G34R/V tumours formed a highly distinct methylation subgroup marked by global hypomethylation. They are enriched in several whole chromosomal arm DNA copy number losses, which at 4q appears to converge along with somatic mutation on the F-box protein family member FBXW7, known to play a role in MYCN stabilization. MYCN was previously identified to be differentially bound by H3K36me3, and we further identified a novel MYCN signature to be highly expressed in H3.3G34R/V tumours. Expression of the H3.3G34R/V mutation in pGBM cells leads to loss of H3K36me3 in cis, and differential genomic binding of the activating mark globally. This appears linked to distinct H3K36me3 enhancer profiles by ChIP-seq, with consistent targeting of lysine 36 demethylases KDM2A/KDM4A. Additional super-enhancers identified in H3G34R/V cells include NOTCH1 and SF3A2, with both Notch signalling and splicing factor gene expression signatures significantly upregulated in patient samples. Screening against a library of >400 chemotherapeutics and small molecules identified a specific dependency for H3.3G34R/V cells on several agents targeting AURKA (as previously linked to MYCN upregulation) but also multiple chemotypes of proteasome inhibitors and the survivin inhibitor YM155. These data identify new rationally-based therapeutic options for exploration in this subset of paediatric/young adult GBM.
IMMU-72. TARGETING GLIOBLASTOMA STEM CELLS USING A SECOND-GENERATION EGFRvIII SPECIFIC PEPTIDE VACCINE STRATEGY
Authors: Mario Fidanza, Puja Gupta, Svenja Pahlke, Albert Wong
Journal: Neuro-Oncology (2018)

A large proportion of GBM tumors express an altered, constitutively active version of the EGF receptor referred to as EGFRvIII. Along with increasing proliferation and inhibiting apoptosis, expression of EGFRvIII is also a GBM stem cell marker. Targeting tumor stem cells based on EGFRvIII expression may therefore improve survival for GBM patients. As such, several clinical trials using a peptide vaccine directed against EGFRvIII have shown promising results. We have explored improved versions of our original EGFRvIII peptide vaccine and have identified a candidate that shows a 60% improvement in murine subcutaneous tumor models. In this study, we further assessed the efficacy of this 2nd generation vaccine in a murine GL261 intracranial tumor model. Mice that received the EGFRvIII peptide vaccine survived 40% longer (median) than non-vaccinated mice. This response required both CD4+ and CD8+ T cells as the observed survival benefit was lost when either of these cell populations was depleted. The specificity of this vaccine strategy was valicated by an in vitro cytotoxicity assay which demonstrated that T cells derived from EGFRvIII peptide vaccinated mice were capable of specifically killing EGFRvIII expressing GL261 target cells in vitro, while demonstrating no cytotoxitiy against EGFRvIII negative cells. Treatment with the peptide vaccine increased the abundance of tumor infiltrating CD8+ T cells (p=0.0017) and altered the intra-tumoral CD4+ to CD8+ cell ratio (p=0.0015). Moreover, relative to control mice, tumor infiltrating CD8+ T cells in vaccinated mice show significant expression of the conventional immune checkpoint receptor PD-1, indicating that combinational therapies may potentiate the vaccine induced survival benefit in this model. We are currently assessing the utility of both adjuvant and immunomodulatory combinations in an attempt to further increase the efficacy of this second generation peptide vaccine.
Abstract 15535: Reclassification and Hemodynamic Correlations of Patients With Diastolic Dysfunction Based on Updated Left Ventricular Diastolic Dysfunction Guidelines
Authors: Kimi Sato, Andrew D Grant, Kazuaki Negishi, Tomoko Negishi, Arnav Kumar, Paul Cremer, Patrick Collier, Samir R Kapadia, Richard A Grimm, Milind Y Desai, Brian P Griffin, Zoran B Popovic
Journal: Circulation (2016)

Background: An updated 2016 echocardiographic algorithm for diagnosing left ventricular (LV) diastolic dysfunction (DD) was recently proposed. We aimed to compare the hemodynamic correlations of new echocardiographic LVDD grading algorithm to the 2009 version. Methods: We retrospectively studied patients free of atrial fibrillation or significant mitral valve disease who underwent transthoracic echocardiography while in normal sinus rhythm within 24 hours of elective heart catheterization between January 2008 and October 2010. Left ventricular end-diastolic pressure (LVEDP), the time constant of isovolumic pressure decay (Tau), and end-diastolic volume index at a pressure of 20mmHg (EDVi20) were determined. Results: A total of 460 patients were identified (mean age 63 ± 13years; 61% male; mean LVEF 55 ± 13%, 28% with LVEDP ≥20 mmHg).The 2009 LVDD Guidelines classified 55 patients (12%) as normal diastolic function, 132 (29%) as grade 1, 156 (34%) as grade 2, and 117 (25%) as grade 3 DD. Based on 2016 Guid...