Refine
Has Fulltext
- yes (45)
Is part of the Bibliography
- yes (45)
Year of publication
Document Type
- Journal article (41)
- Doctoral Thesis (2)
- Conference Proceeding (1)
- Preprint (1)
Keywords
- HNSCC (4)
- biodiversity (3)
- head and neck cancer (3)
- HGF (2)
- Met (2)
- Translational research (2)
- cancer metabolism (2)
- insects (2)
- protease inhibitors (2)
- survival (2)
Institute
- Medizinische Klinik und Poliklinik II (10)
- Theodor-Boveri-Institut für Biowissenschaften (8)
- Klinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie (7)
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenkrankheiten, plastische und ästhetische Operationen (4)
- Pathologisches Institut (4)
- Comprehensive Cancer Center Mainfranken (3)
- Institut für Physikalische und Theoretische Chemie (3)
- Medizinische Klinik und Poliklinik I (3)
- Institut für Klinische Epidemiologie und Biometrie (2)
- Institut für Pharmazie und Lebensmittelchemie (2)
Sonstige beteiligte Institutionen
The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874
Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors.
Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.
Purpose
Integrating moderate hypofractionation to the macroscopic tumor with elective nodal irradiation while sparing the organs at risk (OAR) in chemoradiotherapy of locally advanced non-small-cell lung cancer.
Methods
From 2010-2018, treatment, patient and tumor characteristics of 138 patients from two radiation therapy centers were assessed. Chemoradiotherapy by intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) to the primary tumor and macroscopic lymph node metastases was used.
Results
A total of 124 (90%) patients received concurrent chemotherapy. 106 (76%) patients had UICC (Union for International Cancer Control) stage ≥IIIB and 21 (15%) patients had an oligometastatic disease (UICC stage IV). Median SIB and elective total dose was 61.6 and 50.4 Gy in 28 fractions, respectively. Furthermore, 64 patients (46%) had an additional sequential boost to the primary tumor after the SIB-IMRT main series: median 6.6 Gy in median 3 fractions. The median cumulative mean lung dose was 15.6 Gy (range 6.2-29.5 Gy). Median follow-up and radiological follow-up for all patients was 18.0 months (range 0.6-86.9) and 16.0 months (range 0.2-86.9), respectively. Actuarial local control rates at 1, 2 and 3 years were 80.4, 68.4 and 57.8%. Median overall survival and progression-free survival was 30.0 months (95% confidence interval [CI] 23.5-36.4) and 12.1 months (95% CI 8.2-16.0), respectively. Treatment-related toxicity was moderate. Radiation-induced pneumonitis grade 2 and grade 3 occurred in 13 (9.8%) and 3 (2.3%) patients.
Conclusions
Chemoradiotherapy using SIB-IMRT showed promising local tumor control rates and acceptable toxicity in patients with locally advanced and in part oligometastatic lung cancer. The SIB concept, resulting in a relatively low mean lung dose, was associated with low numbers of clinically relevant pneumonitis. The overall survival appears promising in the presence of a majority of patients with UICC stage ≥IIIB disease.
Objectives: The purpose of this study was to investigate the development of lateralization skills in children who received bilateral cochlear implants (CIs) in sequential operations. Methods: The lateralization skills of 9 children with a mean age of 4.1 years at the first surgery and 5.5 years at the second surgery were assessed at 3 time intervals. Children were assessed with a 3-loudspeaker setup (front, left and right) at 0.9 years (interval I) and 1.6 years (interval II) after the second implantation, and after 5.3 years of bilateral implant use (interval III) with a 9-loudspeaker setup in the frontal horizontal plane between -90° and 90° azimuth. Results: With bilateral implants, a significant decrease in lateralization error was noted between test interval I (45.0°) and II (23.3°), with a subsequent significant decrease at test interval III (4.7°). Unilateral performance with the CI did not improve significantly between the first 2 intervals; however, there was a bias of responses towards the unilateral side by test interval III. Conclusions: The lateralization abilities of children with bilateral CIs develop in a relatively short period of time (1-2 years) after the second implant. Children appear to be able to acquire binaural skills after bilateral cochlear implantation.
Auditory Brainstem Implantation Improves Speech Recognition in Neurofibromatosis Type II Patients
(2013)
This prospective study aimed to determine speech understanding in neurofibromatosis type II (NF2) patients following implantation of a MED-EL COMBI 40+ auditory brainstem implant (ABI). Patients (n = 32) were enrolled postsurgically. Nonauditory side effects were evaluated at fitting and audiological performance was determined using the Sound Effects Recognition Test (SERT), Monosyllable-Trochee-Polysyllable (MTP) test and open-set sentence tests. Subjective benefits were determined by questionnaire. ABI activation was documented in 27 patients, 2 patients were too ill for testing and 3 patients were without any auditory perception. SERT and MTP outcomes under auditory-only conditions improved significantly between first fitting and 12-month follow-up. Open-set sentence recognition improved from 5% at first fitting to 37% after 12 months. The number of active electrodes had no significant effect on performance. All questionnaire respondents were ‘satisfied' to ‘very satisfied' with their ABI. An ABI is an effective treatment option in NF2 patients with the potential to provide open-set speech recognition and subjective benefits. To our knowledge, the data presented herein is exceptional in terms of the open-set speech perception achieved in NF2 patients.
Objectives: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. Methods: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. Results: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. Conclusions: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music.
Background
Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases.
Case presentation
The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved.
Conclusions
Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.
The reliability of implantable blood sensors is often hampered by unspecific adsorption of plasma proteins and blood cells. This not only leads to a loss of sensor signal over time, but can also result in undesired host vs. graft reactions. Within this study we evaluated the hemocompatibility of isocyanate conjugated star shaped polytheylene oxide-polypropylene oxide co-polymers NCO-sP(EO-stat-PO) when applied to gold surfaces as an auspicious coating material for gold sputtered blood contacting sensors. Quartz crystal microbalance (QCM) sensors were coated with ultrathin NCO-sP(EO-stat-PO) films and compared with uncoated gold sensors. Protein resistance was assessed by QCM measurements with fibrinogen solution and platelet poor plasma (PPP), followed by quantification of fibrinogen adsorption. Hemocompatibility was tested by incubation with human platelet rich plasma (PRP). Thrombin antithrombin-III complex (TAT), beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were used as coagulation activation markers. Furthermore, scanning electron microscopy (SEM) was used to visualize platelet adhesion to the sensor surfaces. Compared to uncoated gold sensors, NCO-sP(EO-stat-PO) coated sensors revealed significant better resistance against protein adsorption, lower TAT generation and a lower amount of adherent platelets. Moreover, coating with ultrathin NCO-sP(EO-stat-PO) films creates a cell resistant hemocompatible surface on gold that increases the chance of prolonged sensor functionality and can easily be modified with specific receptor molecules.
The novel BackHome system offers individuals with disabilities a range of useful services available via brain-computer interfaces (BCIs), to help restore their independence. This is the time such technology is ready to be deployed in the real world, that is, at the target end users’ home. This has been achieved by the development of practical electrodes, easy to use software, and delivering telemonitoring and home support capabilities which have been conceived, implemented, and tested within a user-centred design approach. The final BackHome system is the result of a 3-year long process involving extensive user engagement to maximize effectiveness, reliability, robustness, and ease of use of a home based BCI system. The system is comprised of ergonomic and hassle-free BCI equipment; one-click software services for Smart Home control, cognitive stimulation, and web browsing; and remote telemonitoring and home support tools to enable independent home use for nonexpert caregivers and users. BackHome aims to successfully bring BCIs to the home of people with limited mobility to restore their independence and ultimately improve their quality of life.
Introduction:
Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting.
Methods:
Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results:
A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm)
Background:
Recent decades have seen a rise in the incidence of well-differentiated (mainly papillary) thyroid carcinoma around the world. In Germany, the age-adjusted incidence of well-differentiated thyroid carcinoma in 2010 was 3.5 per 100 000 men and 8.7 per 100 000 women per year.
Method:
This review is based on randomized, controlled trials and multicenter trials on the treatment of well-differentiated thyroid carcinoma that were retrieved by a selective literature search, as well as on three updated guidelines issued in the past two years.
Results:
The recommended extent of surgical resection depends on whether the tumor is classified as low-risk or high-risk, so that papillary microcar cinomas, which carry a highly favorable prognosis, will not be overtreated. More than 90% of localized, well-differentiated thyroid carcinomas can be cured with a combination of surgery and radioactive iodine therapy. Radio active iodine therapy is also effective in the treatment of well-differentiated thyroid carcinomas with distant metastases, yielding a 10-year survival rate of 90%, as long as there is good iodine uptake and the tumor goes into remission after treatment; otherwise, the 10-year survival rate is only 10%. In the past two years, better treatment options have become available for radioactive-iodine-resistant thyroid carcinoma. Phase 3 studies of two different tyrosine kinase inhibitors have shown that either one can markedly prolong progression-free survival, but not overall survival. Their more common clinically significant side effects are hand-foot syndrome, hypertension, diarrhea, proteinuria, and weight loss.
Conclusion:
Slow tumor growth, good resectability, and susceptibility to radioactive iodine therapy lend a favorable prognosis to most cases of well-differentiated thyroid carcinoma. The treatment should be risk-adjusted and interdisciplinary, in accordance with the current treatment guidelines. Even metastatic thyroid carcinoma has a favorable prognosis as long as there is good iodine uptake. The newly available medical treatment options for radioactive-iodine-resistant disease need to be further studied.
We demonstrate two-quantum (2Q) coherent two-dimensional (2D)electronic spectroscopy using a shot-to-shot-modulated pulse shaper and fluorescence detection. Broadband collinear excitation is realized with the supercontinuum output of an argon-filled hollow-core fiber, enabling us to excite multiple transitions simultaneously in the visible range. The 2Q contribution is extracted via a three-pulse sequence with 16-fold phase cycling and simulated employing cresyl violet as a model system. Furthermore, we report the first experimental realization of one-quantum−two-quantum (1Q-2Q) 2D spectroscopy, offering less congested spectra as compared with the 2Q implementation. We avoid scattering artifacts and nonresonant solvent contributions by using fluorescence as the observable. This allows us to extract quantitative information about doubly excited states that agree with literature expectations. The high sensitivity and background-free nature of fluorescence detection allow for a general applicability of this method to many other systems.
Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) γ-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA).While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms.
5. Würzburger Wirtschaftssymposium, 20.11.2008 Deutsche Erfindungen verändern die Welt - heute wie vor 500 Jahren. Von Buchdruck, über Dieselmotor, Glühbirne bis hin zu Airbag, Aspirin, Dübel, Fernseher und mp3-Format. Alleine dieser bescheidene Überblick des Phänomens “Made in Germany” lässt den Betrachter die Bedeutung und das Potenzial von Innovationen am Standort Deutschland schnell erkennen. Experten aus Wirtschaft, Politik und Gesellschaft setzten sich am 20.11.2008 unter der Leitfrage: “Innovationen – Performancetreiber und nachhaltiger Wirtschaftsmotor in Deutschland?” mit der Bedeutung von Innovationen für den Standort Deutschland auseinander. Die Festschrift rundet - neben Interviews mit und Gastbeiträgen von Referenten der Veranstaltung - das 5. Würzburger Wirtschaftssymposium mit Stellungnahmen und Beiträgen renommierter Experten ab. Zu Wort kommen dabei Jungunternehmer ebenso wie Wissenschaftler der Universität Würzburg und Vertreter externer Organisationen.
This thesis describes novel concepts for the measurement of the static and dynamic properties of the electronic structure of molecules and nanocrystals in the liquid phase by means of coherent fluorescence-detected spectroscopy in two and three frequency dimensions. These concepts are based on the systematic variation ("phase cycling") of a sequence of multiple time-delayed femtosecond excitation pulses in order to decode a multitude of novel nonlinear signals from the resulting phase-dependent fluorescence signal. These signals represent any permutation of correlations between zero-, one-, two-, and three-quantum coherences. To this end, two new phase-cycling schemes have been developed which can simultaneously resolve and discriminate several nonlinear signals of sixth order, including those of the fourth order of nonlinearity.
By means of the sixth-order signals recorded in this work, static properties of highly excited electronic states in molecules such as their energies, transition dipole moments, and relative displacement of electronic potential surfaces, as well as dynamic properties in terms of their relaxation kinetics, can be ascertained. Furthermore, it was shown that these signals are suitable for the characterization of exciton-exciton correlations in colloidal quantum dots and for the measurement of ultrafast exciton-exciton annihilation in molecular aggregates.
The experiments performed in this thesis mark an important step towards the complete characterization of the nonlinear response of quantum systems. In view of this, the concept of fluorescence-detected multiple-quantum coherence multidimensional spectroscopy introduced here offers a unified, systematic approach.
In virtue of the technical advantages such as the use of a single excitation beam and the absence of nonresonant contributions, the measurement protocols developed here can be directly transferred to other incoherent observables and to sample systems in other states of matter. Furthermore, the approaches presented here can be systematically extended to higher frequency dimensions and higher orders of nonlinearity.
The 06 serogroup Escherichia coli strain 536 carries two hemolysin (hly) determinants integrated into the chromosome. The two hly determinants are not completely identical, either functionally or structurally, as demonstrated by spontaneous deletion mutants carrying only one of them and by cloning each of the two determinants separately into cosmid vectors. Each hly determinant is independently deleted at a frequency of 10-4 , leading to variants which exhibit similar levels of internal hemolysin but different amounts of secreted hemolysin. The two hly determinants were also identified in the 04 E. coli strain 519. The three E. coli strains 251, 764, and 768, which belong to the serogroup 018, and the 04 strain 367 harbor a single chromosomal hly determinant, as demonstrated by hybridization with hly-gene-specific probes. However, a hybridization probe derived from a sequence adjacent to the hlyC-proximal end of the plasmid pHlyl52-encoded hly determinant hybridizes with several additional chromosomal bands in hemolytic 018 and 06 E. coli strains and even in E. coli K-12. The size ofthe probe causing the multiple hybridization suggests a 1,500- to 1,800-base pair sequence directly flanking hlyC. Spontaneous hemolysin-negative mutants were isolated from strains 764 and 768, which had lost the entire hly determinant but retained all copies of the hlyC-associated sequence. This sequence is not identical to a previously identified (J. Hacker, S. Knapp, and W. Goebel, J. Bacteriol. 154:1145-1154, 1983) somewhat smaller (about 850 base pairs) sequence flanking the other (hlyBb-proximal) end of the plasmid pHlyl52-encoded hly determinant which, as shown here, exists also in multiple copies in these hemolytic E. coli strains and in at least two copies in E. coli K-12. In contrast to the plasmid-encoded hly determinant which is directly flanked at both ends by these two diJJerent sequences, the chromosomal hly determinants are not immediately flanked by such sequences.
Wirkspektrum und Signaltransduktionsmechanismus von oxidierten Lipiden in Arabidopsis thaliana
(2009)
Die endogen in Pflanzen radikalisch gebildeten Phytoprostane regulieren in Arabidopsis thaliana eine Reihe von Genen, die an den Prozessen der Detoxifizierung und Zellproliferation beteiligt sind, während die externe Applikation dieser Oxylipine in vitro eine Akkumulation von sekundären Metaboliten, sogenannten Phytoalexinen, nach sich zieht. Ferner war aus vorherigen Arbeiten des Lehrstuhls für Pharmazeutische Biologie bekannt, dass die Vorbehandlung mit Phytoprostanen in Arabidopsis thaliana eine Schutzwirkung gegen nachfolgenden oxidativen Stress vermittelt. Neben nicht-enzymatisch gebildeten Oxylipinen akkumulieren in höheren Pflanzen als Antwort auf einen oxidativen Stress auch enzymatisch gebildete Oxylipine wie 12-Oxophytodiensäure (OPDA) und Jasmonsäure (JA). Als Ausgangspunkt zur systematischen Analyse der von einzelnen Phytoprostanen vermittelten Wirkspektren diente in der vorliegenden Arbeit eine Transkriptionsanalyse unter Verwendung einer mixotrophen Arabidopsis thaliana Zellkultur nach Phytoprostan-A1 (PPA1)-Behandlung. In weiterführenden Experimenten wurde das durch PPA1-vermittelte Genexpressionsprofil mit dem Profil von weiteren, nicht-enzymatischen sowie dem durch die enzymatisch gebildeten Oxylipine OPDA bzw. JA hervorgerufenen Genexpressionsprofil verglichen. Die Vergleiche zeigten signifikante Übereinstimmungen, aber auch deutliche Unterschiede im Wirkprofil einzelner enzymatischer bzw. nicht-enzymatischer Oxylipine. Das Wirkungsspektrum der radikalisch gebildeten PPA1 überschneidet sich zu 40 Prozent mit dem der enzymatisch gebildeten OPDA, jedoch nur zu sieben Prozent mit dem Wirkspektrum der ebenfalls enzymatisch gebildeten JA. Diese Beobachtung ließ einen über strukturelle Merkmale vermittelten Signalmechanismus vermuten, da die chemischen Strukturen von PPA1 und OPDA, nicht jedoch PPA1 und JA, verwandt sind. Zur Überprüfung der vorstehenden Hypothese wurden die Promotorbereiche der durch PPA1 mehr als dreifach induzierten Gene bioinformatisch auf häufig vorhandene Sequenzmotive untersucht. Es zeigte sich, dass etwa die Hälfte der Promotorbereiche der durch PPA1 induzierten Gene ein Bindungsmotiv für TGA-Transkriptionsfaktoren enthält. Nachfolgende Transkriptomanalysen in der TGA-Dreifach knockout Arabidopsis thaliana Mutante tga2tga5tga6 zeigten, dass 60 Prozent der PPA1- bzw. 30 Prozent der ODPA-vermittelten Genexpression durch die TGA-Transkriptionsfaktoren TGA2, TGA5 und TGA6 vermittelt werden. Neben übereinstimmenden Wirkungen von PPA1 und OPDA in der Genexpression sind in der Literatur überschneidende Wirkungen von OPDA und JA bezüglich einer Wurzelwachstumshemmung in Arabidopsis thaliana beschrieben. In Experimenten zur Untersuchung des Wurzelwachstums resultierte die exogene Applikation von JA bzw. OPDA auf Arabidopsis thaliana Samen in einer Hemmung des Wurzelwachstums um 63 bzw. 72 Prozent. Dagegen vermittelte PPA1 nur eine Hemmung um 50 Prozent. Die vorstehend beschriebenen Wirkungen verschiedener Phytoprostane belegen ein umfassendes Wirkspektrum dieser heterogenen Substanzklasse. Neben den in vorliegender Arbeit im Vordergrund stehenden Phytoprostan-vermittelten Stressreaktionen sind eine Reihe physiologischer Prozesse, darunter das Wurzelwachstum, zumindest teilweise durch Phytoprostane reguliert. Ferner konnte in der der vorliegenden Arbeit erstmalig gezeigt werden, dass mindestens zwei der durch Phytoprostane induzierten Gene Proteine kodieren, die effizient die Metabolisierung von Phytoprostanen fordern, um oxidativen Schäden vorzubeugen. Vermittelt werden die Phytoprostan- Wirkungen unter anderem durch die TGA-Transkriptionsfaktoren TGA2, TGA5 und TGA6, welche zur Expression von Detoxifizierungs- und Stressgenen führen.
The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874)
Introduction
Spindle cell rhabdomyosarcoma of the head and neck is a very rare tumor in adults. We report on one case with long-term survival.
Case presentation
A 41-year-old nonsmoking Caucasian man presented in June 2007 with a painless swelling under his tongue. A diagnosis of a soft tissue sarcoma, and a myofibrosarcoma in particular, was made via biopsy. After multimodal treatment, including local and systemic therapy, our patient remained disease-free until September 2010. The local recurrence was treated unsuccessfully with various chemotherapy regimens. In September 2011, our patient underwent surgical resection again, and a spindle cell rhabdomyosarcoma was diagnosed. To analyze the mismatch between the original diagnosis of a myofibrosarcoma and the second diagnosis, the two specimens were reassessed, and a final diagnosis of a spindle cell rhabdomyosarcoma was made. In 2012 and 2013, our patient suffered further recurrences that were surgically treated, and he is still alive with disease six years and 10 months after the initial diagnosis in June 2007.
Conclusions
In adults, the spindle cell rhabdomyosarcoma tumor is very rare in the head and neck region. In contrast to childhood tumors, spindle cell rhabdomyosarcoma in adulthood is often associated with a poor prognosis. In the present case, the radical surgical treatment might have helped to prolong the patient’s overall survival, which has lasted more than six years. To our knowledge, this is the longest overall survival reported so far for this tumor entity in the head and neck region.