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Search Results: 1 - 10 of 30983 matches for " Thomas Kissel "
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Low Molecular Weight pDMAEMA-block-pHEMA Block-Copolymers Synthesized via RAFT-Polymerization: Potential Non-Viral Gene Delivery Agents?
Olga Samsonova,Christian Pfeiffer,Markus Hellmund,Olivia M. Merkel,Thomas Kissel
Polymers , 2011, DOI: 10.3390/polym3020693
Abstract: The aim of this study was to investigate non-viral pDNA carriers based on diblock-copolymers consisting of poly(2-(dimethyl amino)ethyl methacrylate) (pDMAEMA) and poly(2-hydroxyethyl methacrylate) (pHEMA). Specifically the block-lengths and molecular weights were varied to determine the minimal requirements for transfection. Such vectors should allow better transfection at acceptable toxicity levels and the entire diblock-copolymer should be suitable for renal clearance. For this purpose, a library of linear poly(2-(dimethyl amino)ethyl methacrylate- block-poly(2-hydroxyl methacrylate) (pDMAEMA -block-pHEMA) copolymers was synthesized via RAFT (reversible addition-fragmentation chain transfer) polymerization in a molecular weight (Mw) range of 17–35.7 kDa and analyzed using 1H and 13C NMR (nuclear magnetic resonance), ATR (attenuated total reflectance), GPC (gel permeation chromatography) and DSC (differential scanning calorimetry). Copolymers possessing short pDMAEMA-polycation chains were 1.4–9.7 times less toxic in vitro than polyethylenimine (PEI) 25 kDa, and complexed DNA into polyplexes of 100–170 nm, favorable for cellular uptake. The DNA-binding affinity and polyplex stability against competing polyanions was comparable with PEI 25 kDa. The zeta-potential of polyplexes of pDMAEMA-grafted copolymers remained positive (+15–30 mV). In comparison with earlier reported low molecular weight homo pDMAEMA vectors, these diblock-copolymers showed enhanced transfection efficacy under in vitro conditions due to their lower cytotoxicity, efficient cellular uptake and DNA packaging. The homo pDMAEMA 115 (18.3 kDa) self-assembled with DNA into small positively charged polyplexes, but was not able to transfect cells. The grafting of 6 and 57 repeating units of pHEMA (0.8 and 7.4 kDa) to pDMAEMA 115 increased the transfection efficacy significantly, implying a crucial impact of pHEMA on vector-cell interactions. The intracellular trafficking, in vivo transfection efficacy and kinetics of low molecular weight pDMAEMA -block-pHEMA are subject of ongoing studies.
Quantification of the internalization patterns of superparamagnetic iron oxide nanoparticles with opposite charge
Christoph Schweiger, Raimo Hartmann, Feng Zhang, Wolfgang J. Parak, Thomas H. Kissel, Pilar Rivera_Gil
Journal of Nanobiotechnology , 2012, DOI: 10.1186/1477-3155-10-28
Abstract: The physicochemical characterization of the nanoparticles showed particles of approximately the same size and shape as well as similar magnetic properties, only differing in charge due to different surface coatings. Incubation of the cells with both nanoparticles resulted in strong differences in the internalization rate and in the intracellular localization depending on the charge. Quantitative and qualitative analysis of nanoparticles-organelle colocalization experiments revealed that positively charged particles were found to enter the cells faster using different endocytotic pathways than their negative counterparts. Nevertheless, both nanoparticles species were finally enriched inside lysosomal structures and their efficiency in agarose phantom relaxometry experiments was very similar.This quantitative analysis demonstrates that charge is a key factor influencing the nanoparticle-cell interactions, specially their intracellular accumulation. Despite differences in their physicochemical properties and intracellular distribution, the efficiencies of both nanoparticles as MRI agents were not significantly different.
Prospektive, offene, multizentrische Kohortenstudie (AWB) zur Wirksamkeit und Vertr glichkeit von Estradiolvalerat/Norethisteron (Merigest) bei klimakterischen Beschwerden.
Zahradnik HP,Kissel C
Journal für Menopause , 2004,
Abstract: In der hier vorgestellten prospektiven, offenen, multizentrischen Anwendungsbeobachtung (AWB) wurden Daten zur Wirksamkeit und Vertr glichkeit von kontinuierlich-kombiniertem Estradiol/Norethisteron (Merigest) unter Routinebedingungen bei Frauen mit klimakterischen Beschwerden gesammelt. Zwischen Anfang Oktober 2002 und Ende September 2003 wurden in 157 gyn kologischen Arztpraxen zu 98,7 % jeweils drei Patientinnen in die Studie eingebracht und meistens über neun Monate beobachtet. Der Schweregrad klimakterischer Beschwerden bzw. Wirksamkeit von Merigest wurden anhand eines Fragebogens, der in seinem Aufbau einer Anamneseerhebung angepa t wurde, erfa t, den die Patientin selbst vor Behandlungsbeginn, sowie 3, 6 und 9 Monate nach Behandlungsbeginn ausfüllte. Insgesamt war dieser Fragebogen aus der Menopausenbewertungsskala (MRS II) abgeleitet. Ferner wurde über den gesamten Behandlungszeitraum hinweg die Vertr glichkeit durch Dokumentation unerwünschter Ereignisse analysiert. 468 Beobachtungsb gen konnten ausgewertet werden. 65 % der Patientinnen waren zwischen 50 und 59 Jahre alt, 13,9 % unter 50, 21,1 % über 60. 12,6 % (n = 59) der Patientinnen haben die AWB vorzeitig beendet, nur 13 Frauen wegen Nebenwirkungen. 69 % der Patientinnen gaben eine vollst ndige Remission, ca. 90 % eine Besserung, 3,9 % noch mittelschwere und 1,5 % noch schwere Hitzewallungen nach durchschnittlich neunmonatiger Merigest-Behandlung an. Auch Nervosit t/Reizbarkeit, depressive Verstimmungen/ ngstlichkeit, Müdigkeit/Antriebslosigkeit, Herzbeklemmung/Herzrasen und vor allem Schlafst rungen waren bei mehr als 2/3 der Patientinnen signifikant gebessert. Wahrscheinlich durch die Verminderung der Scheidentrockenheit konnte auch in ca. 20 % der F lle eine Besserung des sexuellen Verlangens registriert werden, wenn zuvor Probleme bestanden. In der globalen Beurteilung der Wirksamkeit wurde Merigest von 97,6 % der rzte und 93,7 % der Patientinnen als "sehr gut" und "gut" eingestuft, bei der Beurteilung der Vertr glichkeit votierten 99,0 % der rzte und 96,3 % der Patientinnen mit "sehr gut" und "gut". Im Verlauf der AWB wurde von 30,8 % (n = 144) der Patientinnen Brustspannen als spezifische Nebenwirkung am h ufigsten angegeben, allerdings in über 3/4 der F lle als leicht eingestuft und vor allem w hrend der ersten drei Monate. Im übrigen wurden nur bei 3,2 % der Patientinnen sonstige, unspezifische Nebenwirkungen registriert, wie z. B. deme, übelkeit und Hautausschlag. Insgesamt sprechen die hier vorgestellten Daten dieser AWB für eine gute Wirksamkeit und Vertr glichkeit von Merige
Dystextia: An Early Sign of Pregnancy-Associated Meningioma  [PDF]
James B. Hannah, Phillip Kissel, Bianca Russell, Jo Ellen Hose
Open Journal of Modern Neurosurgery (OJMN) , 2014, DOI: 10.4236/ojmn.2014.42015
Abstract: Objective: The authors report a case of meningioma causing incomprehensible and excessive text messaging in a postpartum woman. Case Report: We report the case of expressive dystextia related to a postpartum, progesterone receptor-positive meningioma. Growth of meningiomas can accelerate during pregnancy and the postpartum period due to expression of hormone receptors, particularly progesterone. This is the first study describing dystextia related to a brain tumor; previous cases of dystextia are associated with stroke and complex migraine. Here expressive dystextia, the inability to compose syntactically comprehensible text messages, preceded acute neurologic signs by several months, and surgical resection of the meningioma eliminated all neurologic sequelae. Possible genetic etiologies for meningioma are discussed since this patient’s prior thyroid cancer at age 18 suggests a relationship between the two neoplasms. Conclusions: Since text messaging is becoming one of the principal forms of communication in our society and requires both cognitive and motor skills, clinicians should be aware that dystextia may be the initial sign of significant neurologic pathology. We propose that an inquiry about altered text messaging frequency and comprehensibility should be a standard part of the neurologic evaluation.
p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus
Thomas G. Paulson, Patricia C. Galipeau, Lianjun Xu, Heather D. Kissel, Xiaohong Li, Patricia L. Blount, Carissa A. Sanchez, Robert D. Odze, Brian J. Reid
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003809
Abstract: Background Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett's esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions The results of this study suggest the environment of the esophagus in BE patients can both generate and select for clones with p16 mutations.
Feasibility of RNA and DNA Extraction from Fresh Pipelle and Archival Endometrial Tissues for Use in Gene Expression and SNP Arrays
Heather D. Kissel,Thomas G. Paulson,Karen Liu,Xiaohong Li,Elizabeth Swisher,Rochelle Garcia,Carissa A. Sanchez,Brian J. Reid,Susan D. Reed,Jennifer Anne Doherty
Obstetrics and Gynecology International , 2013, DOI: 10.1155/2013/576842
Abstract: Identifying molecular markers of endometrial hyperplasia (neoplasia) progression is critical to cancer prevention. To assess RNA and DNA quantity and quality from routinely collected endometrial samples and evaluate the performance of RNA- and DNA-based arrays across endometrial tissue types, we collected fresh frozen (FF) Pipelle, FF curettage, and formalin-fixed paraffin-embedded (FFPE) hysterectomy specimens (benign indications) from eight women. Additionally, neoplastic and uninvolved tissues from 24 FFPE archival hysterectomy specimens with endometrial hyperplasias and carcinomas were assessed. RNA was extracted from 15 of 16 FF and 51 of 51 FFPE samples, with yields >1.2?μg for 13/15 (87%) FF and 50/51 (98%) FFPE samples. Extracted RNA was of high quality; all samples performed successfully on the Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation (WG-DASL) array and performance did not vary by tissue type. While DNA quantity from FFPE samples was excellent, quality was not sufficient for successful performance on the Affymetrix SNP Array 6.0. In conclusion, FF Pipelle samples, which are minimally invasive, yielded excellent quantity and quality of RNA for gene expression arrays (similar to FF curettage) and should be considered for use in genomic studies. FFPE-derived DNA should be evaluated on new rapidly evolving sequencing platforms. 1. Introduction Though endometrial carcinoma is the most common gynecologic malignant neoplasm [1], diagnostic capabilities and management of endometrial precancer (intraepithelial neoplasia) lag far behind those of cervical carcinoma [2]. A neoplastic continuum from simple, to complex, to atypical hyperplasia, to endometrial carcinoma is suggested from longitudinal epidemiologic studies [3–5]. Identification of molecular alterations present in various stages of endometrial neoplasia will provide the basis for early detection and therapeutics [6]. Present diagnostic capabilities utilizing histologic evaluation for endometrial hyperplasia/neoplasia alone are limited by poor diagnostic reproducibility [7] and relatively low prognostic value. Risk of progression to carcinoma among women with a diagnosis of endometrial hyperplasia with atypia is not well understood, though exposure to progestin therapy has been reported to be associated with an approximately 60% decreased risk of progression [4, 8]. Future studies that attempt to elucidate molecular biomarkers of endometrial hyperplasia progression risk will require the development of two methodologies: the ability to perform array
Local Delivery of Nimodipine by Prolonged-Release Microparticles—Feasibility, Effectiveness and Dose-Finding in Experimental Subarachnoid Hemorrhage
Daniel H?nggi, Jason Perrin, Sven Eicker, Kerim Beseoglu, Nima Etminan, Marcel Alexander Kamp, Hi-Jae Heiroth, Nadia Bege, Stephan Macht, Katrin Frauenknecht, Clemens Sommer, Thomas Kissel, Hans-Jakob Steiger
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042597
Abstract: Background and Purpose To investigate the effect of locally applied nimodipine prolonged-release microparticles on angiographic vasospasm and secondary brain injury after experimental subarachnoid hemorrhage (SAH). Methods 70 male Wistar rats were categorized into three groups: 1) sham operated animals (control), 2) animals with SAH only (control) and the 3) treatment group. SAH was induced using the double hemorrhage model. The treatment group received different concentrations (20%, 30% or 40%) of nimodipine microparticles. Angiographic vasospasm was assessed 5 days later using digital subtraction angiography (DSA). Histological analysis of frozen sections was performed using H&E-staining as well as Iba1 and MAP2 immunohistochemistry. Results DSA images were sufficient for assessment in 42 animals. Severe angiographic vasospasm was present in group 2 (SAH only), as compared to the sham operated group (p<0.001). Only animals within group 3 and the highest nimodipine microparticles concentration (40%) as well as group 1 (sham) demonstrated the largest intracranial artery diameters. Variation in vessel calibers, however, did not result in differences in Iba-1 or MAP2 expression, i.e. in histological findings for secondary brain injury. Conclusions Local delivery of high-dose nimodipine prolonged-release microparticles at high concentration resulted in significant reduction in angiographic vasospasm after experimental SAH and with no histological signs for matrix toxicity.
SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy
John T. Kissel,Charles B. Scott,Sandra P. Reyna,Thomas O. Crawford,Louise R. Simard,Kristin J. Krosschell,Gyula Acsadi,Bakri Elsheik,Mary K. Schroth,Guy D'Anjou,Bernard LaSalle,Thomas W. Prior,Susan Sorenson,Jo Anne Maczulski,Mark B. Bromberg,Gary M. Chan,Kathryn J. Swoboda
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021296
Abstract: Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.
Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy
Kathryn J. Swoboda, Charles B. Scott, Sandra P. Reyna, Thomas W. Prior, Bernard LaSalle, Susan L. Sorenson, Janine Wood, Gyula Acsadi, Thomas O. Crawford, John T. Kissel, Kristin J. Krosschell, Guy D'Anjou, Mark B. Bromberg, Mary K. Schroth, Gary M. Chan, Bakri Elsheikh, Louise R. Simard
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005268
Abstract: Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2–3 years, 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p≤0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p≤0.0036) and maximum ulnar CMAP scores (p≤0.0001) increased significantly. Conclusions While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. Trial Registration ClinicalTrials.gov
SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy
Kathryn J. Swoboda,Charles B. Scott,Thomas O. Crawford,Louise R. Simard,Sandra P. Reyna,Kristin J. Krosschell,Gyula Acsadi,Bakri Elsheik,Mary K. Schroth,Guy D'Anjou,Bernard LaSalle,Thomas W. Prior,Susan L. Sorenson,Jo Anne Maczulski,Mark B. Bromberg,Gary M. Chan,John T. Kissel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012140
Abstract: Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.
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