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Purpose Due to improved imaging, oligometastatic prostate cancer (OMPC) is diagnosed more frequently. Growing evidence shows that patients with a limited number of metastases benefit from primary-directed radiotherapy (PDT) as well as from metastasis-directed radiotherapy (MDT). This survey investigates the current treatment practice for OMPC among German-speaking radiation oncologists. Methods Members of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie [DEGRO]) were surveyed regarding their current treatment practice via an anonymous online questionnaire sent by email. The survey included six general items and 14 specific items regarding treatment characteristics. Questionnaires with at least 50% of questions completed were considered for further analysis. Results A total of 204 responses were received (15% response rate), 167 were considered for further analysis. Most respondents stated to be specialized in treating prostate cancer patients and to treat 10–30 patients with OMPC per annum; 97% considered PSMA-PET/CT necessary to define oligometastatic disease. Opinions differed regarding the use of systemic therapies: 63% of the respondents aimed to defer systemic therapy using radiotherapy in OMPC, whereas 37% considered systemic therapy necessary. In the setting of synchronous OMPC, 97% recommended PDT with or without a combination of MDT and/or systemic therapy. For metachronous nodal or bone oligometastatic recurrence, 98 and 99%, respectively, would opt for MDT. The majority would combine MDT with systemic therapy in patients with metachronous oligorecurrence. Respondents recommended normofractionation, hypofractionation, and SBRT for lymph node metastases in 49, 27, and 24%, respectively. No consensus existed regarding the field size for MDT of lymph node metastases. Most respondents preferred > 5 fractions for treatment of bone metastases. Conclusion Local radiotherapy for PDT and MDT is routinely used among respondents of this survey, representing 12% of all German-speaking radiation oncologists. The timing of systemic therapy, fractionation schedules, and field sizes are handled differently and remain an area of active investigation.

Purpose To develop a CT-based radiomic signature to predict biochemical recurrence (BCR) in prostate cancer patients after sRT guided by positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET). Material and methods Consecutive patients, who underwent 68Ga-PSMA11-PET/CT-guided sRT from three high-volume centers in Germany, were included in this retrospective multicenter study. Patients had PET-positive local recurrences and were treated with intensity-modulated sRT. Radiomic features were extracted from volumes of interests on CT guided by focal PSMA-PET uptakes. After preprocessing, clinical, radiomics, and combined clinical-radiomic models were developed combining different feature reduction techniques and Cox proportional hazard models within a nested cross validation approach. Results Among 99 patients, median interval until BCR was the radiomic models outperformed clinical models and combined clinical-radiomic models for prediction of BCR with a C-index of 0.71 compared to 0.53 and 0.63 in the test sets, respectively. In contrast to the other models, the radiomic model achieved significantly improved patient stratification in Kaplan-Meier analysis. The radiomic and clinical-radiomic model achieved a significantly better time-dependent net reclassification improvement index (0.392 and 0.762, respectively) compared to the clinical model. Decision curve analysis demonstrated a clinical net benefit for both models. Mean intensity was the most predictive radiomic feature. Conclusion This is the first study to develop a PSMA-PET-guided CT-based radiomic model to predict BCR after sRT. The radiomic models outperformed clinical models and might contribute to guide personalized treatment decisions.

The potential of designing irreversible alkyne-based inhibitors of cysteine cathepsins by isoelectronic replacement in reversibly acting potent peptide nitriles was explored. The synthesis of the dipeptide alkynes was developed with special emphasis on stereochemically homogenous products obtained in the Gilbert-Seyferth homologation for C-C triple bond formation. 23 dipeptide alkynes and 12 analogous nitriles were synthesized and investigated for their inhibition of cathepsins B, L, S and K. Numerous combinations of residues in the P1 and P2 positions as well as terminal acyl groups, allowed for the derivation of extensive structure-activity relationships, which were rationalized by computational covalent docking for selected examples. The determined inactivation constants of the alkynes at the target enzymes span a range of more than three orders of magnitude (3-10,133 M-1s-1). Notably, the selectivity profiles of alkynes do not necessarily reflect those of the nitriles. Inhibitory activity at the cellular level was demonstrated for selected compounds.

Purpose Nodal recurrent prostate cancer (PCa) represents a common state of disease, amenable to local therapy. PSMA-PET/CT detects PCa recurrence at low PSA levels. The aim of this study was to evaluate the outcome of PSMA-PET/CT-based salvage radiotherapy (sRT) for lymph node (LN) recurrence. Methods A total of 100 consecutive patients treated with PSMA-PET/CT-based salvage elective nodal radiotherapy (sENRT) for LN recurrence were retrospectively examined. Patients underwent PSMA-PET/CT scan due to biochemical persistence (bcP, 76%) or biochemical recurrence (bcR, 24%) after radical prostatectomy (RP). Biochemical recurrence-free survival (BRFS) defined as PSA Results Median follow-up was 37 months. Median PSA at PSMA-PET/CT was 1.7 ng/ml (range 0.1–40.1) in patients with bcP and 1.4 ng/ml (range 0.3–5.1) in patients with bcR. PSMA-PET/CT detected 1, 2, and 3 or more LN metastases in 35%, 23%, and 42%, respectively. Eighty-three percent had only pelvic, 2% had only paraaortic, and 15% had pelvic and paraaortic LN metastases. Cumulatively, a total dose converted to EQD21.5 Gy of 66 Gy (60–70 Gy) was delivered to the prostatic fossa, 70 Gy (66–72 Gy) to the local recurrence, if present, 65.1 Gy (56–66 Gy) to PET-positive lymph nodes, and 47.5 Gy (42.4–50.9 Gy) to the lymphatic pathways. Concomitant androgen deprivation therapy (ADT) was administered in 83% of patients. One-, 2-, and 3-year BRFS was 80.7%, 71.6%, and 65.8%, respectively. One-, 2-, and 3-year DMFS was 91.6%, 79.1%, and 66.4%, respectively. In multivariate analysis, concomitant ADT, longer ADT duration (≥ 12 vs. 1 ng/ml) with improved DMFS, respectively. No such association was seen for the number of affected lymph nodes. Conclusions Overall, the present analysis shows that the so far, unmatched sensitivity and specificity of PSMA-PET/CT translates in comparably high BRFS and DMFS after PSMA-PET/CT-based sENRT for patients with PCa LN recurrence. Concomitant ADT, duration of ADT, PSA value before sRT, and localization of LN metastases were significant factors for improved outcome.

To evaluate the feasibility of subsequent elective nodal radiotherapy (ENRT) for nodal recurrences after previous radiotherapy with a defined planning approach for a gapless radiation field junction.Patients with 1) previous radiotherapy of prostate or prostatic fossa and subsequent pelvic ENRT or 2) previous pelvic radiotherapy and subsequent ENRT to paraaortic lymph nodes (LN) and gapless junction of both radiation fields were analyzed. The cumulative maximum dose (DTwenty-two patients with PSMA-PET/CT-staged nodal oligorecurrence after prior radiotherapy were treated with pelvic (14 patients) or paraaortic ENRT (9 patients). One patient was treated sequentially at both locations. Median time between first and second RT was 20.2 months. Median doses to the lymphatic pathways and to PET-positive LN were 47.5 Gy and 64.8 Gy, respectively. The planning constraint of an estimated DENRT for nodal recurrences after a previous radiotherapy with gapless junction of radiation fields seems to be feasible, applying the dose constraints D

Background:: Chiral β-hydroxy esters and α-substituted β-hydroxy esters represent versatile building blocks for pheromones, β-lactam antibiotics and 1,2- or 1,3-aminoalcohols. Objective:: Synthesis of versatile α-substituted β-keto esters and their diastereoselective reduction to the corresponding syn- or anti-α-substituted β-hydroxy esters. Assignment of the relative configuration by NMR-spectroscopy after a Curtius rearrangement of α-substituted β-keto esters to 4-substituted 5-methyloxazolidin-2-ones. Methods: Diastereoselective reduction was achieved by using different Lewis acids (zinc, titanium and cerium) in combination with complex borohydrides as reducing agents. Assignment of the relative configuration was verified by 1H-NMR spectroscopy after Curtius-rearrangement of α-substituted β-hydroxy esters to 4-substituted 5-methyloxazolidin-2-ones. Results:: For the syn-selective reduction, titanium tetrachloride (TiCl4) in combination with a pyridine-borane complex (py BH3) led to diastereoselectivities up to 99% dr. High anti-selective reduction was achieved by using cerium trichloride (CeCl3) and steric hindered reducing agents such as lithium triethylborohydride (LiEt3BH). After Curtius-rearrangement of each α-substituted β-hydroxy ester to the corresponding 4-substituted 5-methyloxazolidin-2-one, the relative configuration was confirmed by 1H NMR-spectroscopy. Conclusion:: We have expanded the procedure of Lewis acid-mediated diastereoselective reduction to bulky α-substituents such as the isopropyl group and the electron withdrawing phenyl ring.

Purpose: This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific-membrane-antigen (PSMA-PET) prior to savage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort. Methods: Patients who underwent 68Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated using and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS. Results: 235 patients with a median follow up (FU) of 24 months were included in the final cohort. 2-years and 4-years BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75%quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1–4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) and only LR confirmed these results. Conclusion The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk-stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensity adaption.

Purpose This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort. Methods Patients who underwent 68 Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS. Results Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1–4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) confirmed these results. Conclusion The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology—Genitourinary.

Background: The APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family-mediated mutagenesis is widespread in human cancers. However, our knowledge of the biological feature and clinical relevance of APOBECs and APOBEC mutagenesis in cancers remains limited. Methods: In this study, with a series of bioinformatic and statistical approaches, we performed a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES) and targeted next-generation sequencing (NGS), transcriptome (bulk RNA-seq and single-cell RNA-seq), immune signatures and immune checkpoint blockade (ICB) potential, patient survival and drug sensitivity, to reveal the distribution characteristics and clinical significance of APOBECs and APOBEC mutagenesis in pan-cancer especially bladder cancer (BLCA). Results: APOBEC mutagenesis dominates in the mutational patterns of BLCA. A higher enrichment score of APOBEC mutagenesis correlates with favorable prognosis, immune activation and potential ICB response in BLCA patients. APOBEC3A and 3B play a significant role in the malignant progression and cell differentiation within the tumor microenvironment. Furthermore, using machine learning approaches, a prognostic APOBEC mutagenesis-related model was established and validated in different BLCA cohorts. Conclusions: Our study illustrates the characterization of APOBECs and APOBEC mutagenesis in multiple cancer types and highlights its potential value as a promising biomarker for prognosis and immunotherapy in BLCA.

Background The aim of this work was to investigate the outcome of metastasis-directed radiotherapy (MDT) in prostate cancer patients with bone metastases following current ESTRO/EORTC subclassifications for oligometastatic disease. Methods Clinical data of 80 consecutive oligometastatic patients with 115 bone lesions receiving MDT between 2011 and 2019 were retrospectively evaluated. Hormone-sensitive (77.5%) and castrate-resistant (22.5%) patients were included. MDT was delivered with conventional fractionated or stereotactic body radiotherapy (SBRT) techniques. Kaplan–Meier method, log rank test, as well as Cox regression were used to calculate local control (LC) and biochemical and clinical progression-free survival (bPFS/cPFS). Results At the time of MDT 31% of patients had de-novo synchronous oligometastatic disease, 46% had de-novo metachronous oligorecurrence after primary treatment and 23% had either de-novo oligoprogressive disease, repeat oligometastatic disease or induced oligometastatic disease. The median BED3 was 93.3 Gy (range 75.8–95.3 Gy). Concomitant ADT was administered in 69% of patients. After a median follow-up of 23 months the median bPFS and cPFS were 16.5 and 21.5 months, respectively. The 2-year LC rate was 98.3%. In multivariate analysis, age ≤ 70 (HR = 2.60, 95% CI 1.20–5.62, p = 0.015) and concomitant ADT (HR = 0.26, 95% CI 0.12–0.58, p = 0.001) significantly correlated with cPFS. Category of oligometastatic disease and hormone-sensitivity were predictive for cPFS in univariate analysis. Of 45 patients with biochemical relapse, nineteen patients (42.2%) had repeat oligometastatic disease. Fourteen patients (31%) underwent a second course of MDT. No patients experienced grade ≥ 3 toxicities. Conclusions MDT is safe and offers high local control rates in bone oligometastases of prostate cancer. At 2 years after treatment, more than 2 out of 5 patients are progression-free. Trial registration Retrospectively registered.

Background Due to improved imaging sensitivity, the term “oligometastatic” prostate cancer disease is diagnosed more often, leading to an increasing interest in metastasis-directed therapy (MDT). There are two types of radiation based MDT applied when treating oligometastatic disease: (1) stereotactic body radiation therapy (SBRT) generally used for bone metastases; or (2) SBRT for isolated nodal oligometastases combined with prophylactic elective nodal radiotherapy. This review aims to summarize current evidence data, which may shed light on the optimal management of this heterogeneous group of patients. Methods A systematic review of the Medline database through PubMed was performed according to PRISMA guidelines. All relevant studies published up to November 2020 were identified and screened. Fifty-six titles were included. Besides outcome parameters, different prognostic and predictive factors were assessed, including site of metastases, time between primary treatment and MDT, use of systemic therapies, hormone sensitivity, as well as pattern of recurrence. Findings Evidence consists largely of retrospective case series and no consistent precise definition of oligometastasis exists, however, most investigators seem to acknowledge the need to distinguish between patients presenting with what is frequently called “synchronous” versus “metachronous” oligometastatic disease. Available data on radiotherapy as MDT demonstrate high local control rates and a small but relevant proportion of patients without progressive disease after 2 years. This holds true for both hormone sensitive and castration resistant prostate cancer diseases. The use of 68Ga-PSMA PET/CT for staging increased dramatically. Radiation doses and field sizes varied considerably among the studies. The search for relevant prognostic and predictive factors is ongoing. Conclusions To our best knowledge this review on oligometastatic prostate cancer included the largest number of original articles. It demonstrates the therapeutic potential and challenges of MDT for oligometastatic prostate cancer. Prospective studies are under way and will provide further high-level evidence.

Enantiomerically pure α-substituted β-hydroxyesters are important chiral building blocks for ligands, auxiliaries and β-lactam antibiotics. A two-step chemo-enzymatic procedure using lipase as biocatalyst is an efficient way to synthesize such products. To date, the methods described are limited to molecules that do not contain a chiral center adjacent to the racemic carbinol, and furthermore, they are limited to acylation. Here, we investigated the deracemization of diastereomerically pure syn- and anti-α-substituted β-hydroxyesters containing two stereo centers, using experimental methods under neat conditions and classical molecule dynamics (MD) simulation. A screening of free and immobilized commercial lipases identified immobilized lipase B from Candida antarctica (Novozyme 435) as the most appropriate biocatalyst for sterically demanding α-substituted β-hydroxyesters. Using Novozyme 435, reaction conditions were optimized and hydroxyesters (3S) or (3R) were achieved with enantiomeric excesses up to ≥99% ee and maximum overall yields of 80%. The absolute configuration of the enantiomers was eventually determined by 1H-NMR spectroscopy after derivatization with Mosher's reagent (α-methoxy-α-trifluoromethylphenylacetic acid = MTPA).

Until recently, alkynes were considered bioinert. Thus, they are popular reaction partners in bioorthogonal click reactions in vitro and in vivo. Despite the virtual chemical inertness of the alkyne moiety, two research groups observed the irreversible inhibition of a cysteine protease by an alkyne functionalised substrate derivative: both EKKEBUS et al. and SOMMER et al. independently described the unexpected inactivation of de-ubiquitinating enzymes by propargylated ubiquitin or ubiquitin-like modifiers bearing propargylamine in place of C-terminal glycine [1, 2]. We intended to harness that finding for the design of inhibitor-based probes for the imaging of tumour-associated cysteine proteases. Cysteine cathepsins play an important role in tumour progression. In particular, cathepsin B is involved in a variety of tumour progression-related processes and an elevated extracellular levels are linked to increased malignancy and poor prognosis [3]. Therefore, this enzyme represents a promising target for the therapy and imaging of tumours. GREENSPAN et al. reported a potent and highly selective, dipeptidyl nitrile-based cathepsin B inhibitor (N-[2-[(3-Carboxyphenyl)methoxy]-1(S)-cyanoethyl]-3-methyl-N2-(2,4-difluorobenzoyl)-L-phenylalaninamide) [4]. Based on that lead compound, cathepsin B-targeting dipeptide alkynes were designed by isoelectronic replacement of the nitrile nitrogen atom by by a methine group and consecutive variation of the 2,4-difluorobenzoyl and (3-carboxybenzyl)oxymethyl residue. Formation of the C-C triple bond by reaction of the corresponding open-chain serine-derived aldehyde with the Bestmann-Ohira reagent was accompanied by partial enantiomerisation. Therefore, the synthesis was performed via Garner’s aldehyde, which accounted for high stereochemical purity of the final compounds. The inhibitory potential was investigated against cathepsins B, S, L and K. The most potent compound exhibited irreversible inhibition of cathepsin B with an inactivation constant (kinact/KI=771 M-1s-1). Values for cathepsins L, S and K were significantly lower; no irreverisible ihibition was observed for cathepsin K. In addition, inhibition of cathepsin B activity in human glioblastoma cell lysates and living cells has been demonstrated. Based on these promising results, dipeptidyl alkynes have the potential to become a valuable tool for imaging due to the expected low activity towards other cysteine proteases. In further studies, selected inhibitors for cathepsin B will be labelled with suitable radionuclides to obtain an inhibitor-based probe directed towards cathepsin B. [1] Ekkebus et al., J. Am. Chem. Soc., 2013, 135, 2867-2870 [2] Sommer et al., Bioorg. Med. Chem., 2013, 21, 2511-2517 [3] Löser and Pietzsch, Front. Chem., 2015, 3:37 [4] Greenspan et al., J. Med. Chem., 2001, 44, 4524-4534.

Der Einsatzbereich von grosen Gasmotoren ist heute auserst vielfaltig. Grundsatzlich wird zwischen mobilen und stationaren Anwendungen unterschieden. Bei stationaren Anwendungen, Schwerpunkt dieser Abhandlung, werden gasbetriebene Verbrennungsmotoren mit einer Leistung von >500 kW heute vor allem zur dezentralen Energieversorgung (Strom oder Strom-Warmekopplung, Bild 1) und zum Antrieb von Kompressoren bei der Forderung und Verteilung von Gas eingesetzt (Verdichterantriebe) [1].

Gasmotoren waren die ersten technisch relevanten Verbrennungsmotoren und spielen heute hauptsachlich im industriellen Einsatz bei der Stromerzeugung, in Blockheizkraftwerken sowie als Verdichterantriebe eine wichtige Rolle. Daneben werden Gasmotoren mehr und mehr in Marineanwendungen als Haupantriebe und Nebenaggregate sowie in Fahrzeugen und Lokomotiven eingesetzt. Bedeutsam sind auch die sogenannten Dual-Fuel-Motoren, die neben Gas auch Diesel oder Schwerol verbrennen konnen. Grosgasmotoren konnen je nach Auslegung eine grose Bandbreite an gasformigen Kraftstoffen umsetzten, neben Erdgas auch Biogase, Deponiegase, Grubengase, Holzgase, Stahlgase und andere technisch erzeugte Gase mit sehr unterschiedlicher Zusammensetzung, Heizwert, Methanzahl und Luftbedarf.

The development of low-emission vehicles requires integrated tools and methods for describing a virtual vehicle and a virtual application. Here the detailed modeling of the combustion process, as it has been further developed by Ricardo, is decisive. This article describes a new tool for calculating the energy release under changing operating conditions. In addition, validation results for stratified charge operation of a turbocharged direct-injection gasoline engine with a jet-directed combustion process.

Die Entwicklung emissionsarmer Fahrzeuge erfordert integrierte Werkzeuge und Methoden zur Darstellung eines virtuellen Fahrzeugs und einer virtuellen Applikation. Entscheidend dabei ist die detaillierte Modellierung der Verbrennung, wie sie von Ricardo weiter entwickelt wurde. In diesem Beitrag wird ein neues Werkzeug zur Berechnung der Energiefreisetzung bei sich andernden Betriebsbedingungen beschrieben, und es werden Validie-rungsergebnisse fur den Schichtladebetrieb eines aufgeladenen DI-Ottomotors mit strahlgefuhrtem Brenn-verfahren vorgestellt.

Gas engines currently have an extremely diverse range of applications. Off-highway gas engines—i.e. engines that are not intended for road vehicles—are increasingly also being used for applications that just a few years ago were the exclusive preserve of diesel engines.

Market trends as well as legislative measures to reduce CO2 emissions significantly require innovative technologies to improve the efficiency of gasoline engines. With this aim, Ricardo’s Lean Boost concept combines direct injection, downsizing by boosting and lean operation under all conditions, however requires a complex exhaust gas aftertreatment system. An alternative approach is Ricardo’s EGR-Boost-technology, featuring charge dilution by recirculated exhaust gas under all operation conditions and thus allowing the use of a conventional three-way-catalyst.

Sowohl der Markt als auch gesetzliche Vorschriften zur deutlichen Absenkung der CO2-Emissionen erfordern innovative Konzepte zur Wirkungsgradsteigerung bei Ottomotoren. Das Lean-Boost-Konzept von Ricardo vereint hierzu die Vorteile von Downsizing durch Aufladung und einem Magerbetrieb in allen Betriebspunkten eines Ottomotors mit Direkteinspritzung, benotigt allerdings ein komplexes Abgasnachbehandlungssystem. Die Alternative ist Ricardos EGR-Boost-Technologie, die eine Ladungsverdunnung durch ruckgefuhrtes Abgas in allen Kennfeldbereichen erlaubt und so auf ein konventionelles Drei-Wege-Katalysatorsystem zuruckgreifen kann.

Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are present in apparently all mammalian cells, but their relevance for the generation of spontaneous cancers remains to be established. Both the 8-oxoG levels and the resulting spontaneous mutations are increased in the livers of Csbm/m/Ogg1−/− mice, which are deficient in the repair of 8-oxoG. In order to determine the consequences of these additional oxidative DNA modifications and mutations and thus assess the tumor initiating potency of this type of endogenous DNA damage, we treated Csbm/m/Ogg1−/− mice and repair-proficient controls with the peroxisome proliferator WY-14,643 (0.025% ad libitum), a potent inducer of liver cell proliferation. The treatment did not generate any additional oxidative DNA damage; the elevated levels of 8-oxoG in the Csbm/m/Ogg1−/− mice even decreased. Also, the spontaneous mutation frequencies observed in the lacI gene of BigBlue Csbm/m/Ogg1−/− mice, which were ∼3-fold higher than in the repair-proficient mice, declined by 39% under the treatment, whereas the frequencies in the livers of the repair-proficient animals remained unchanged. Preneoplastic lesions (staining positive or negative for glucose-6-phoshatase) developed in the livers of both wild-type and Csbm/m/Ogg1−/− mice after 30 weeks. Both the numbers and the total volumes of the lesions were ∼6-fold higher in the repair-deficient mice than in the wild-type mice. The results indicate that spontaneous mutations generated from endogenous oxidative DNA base damage efficiently translate into increased tumorigenesis when cell proliferation is stimulated. [Cancer Res 2007;67(11):5156–61]

Der Einsatzbereich von Gasmotoren ist heute auserst vielfaltig. Off-Highway-betriebene Gasmotoren – also Motoren, die nicht fur Strasenfahrzeuge vorgesehen sind – werden zunehmend auch fur Anwendungen vorgesehen, die noch vor wenigen Jahren fast ausschlieslich mit Dieselmotoren bedient wurden. Gasbetriebene Verbrennungsmotoren mit einer Leistung von > 500 kW werden heute vor allem zur dezentralen Energieversorgung (Strom oder Strom-Warmekopplung), zum Antrieb von Verdichtern bei der Forderung und Verteilung von Gas (Mechanical Drive), aber auch zum Antrieb von zum Beispiel Gastankern (Marine) eingesetzt.

Mitochondrial DNA (mtDNA) is assumed to be highly prone to damage by reactive oxygen species (ROS) because of its location in close proximity to the mitochondrial electron transport chain. Accordingly, mitochondrial oxidative DNA damage has been hypothesized to be responsible for various neurological diseases, ageing and cancer. Since 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most frequent oxidative base modifications, is removed from the mitochondrial genome by the glycosylase OGG1, the basal levels of this lesion are expected to be highly elevated in Ogg1−/− mice. To investigate this hypothesis, we have used a mtDNA relaxation assay in combination with various repair enzymes (Fpg, MutY, endonuclease III, endonuclease IV) to determine the average steady-state number of oxidative DNA modifications within intact (supercoiled) mtDNA from the livers of wild-type mice and those deficient in OGG1 and/or the Cockayne syndrome B (CSB) protein for mice aged up to 23 months. The levels of all types of oxidative modifications were found to be less than 12 per million base pairs, and the difference between wild-type and repair-deficient (Ogg1−/−/Csb−/−) mice was not significant. Thus, the increase of 8-oxoG caused by the repair deficiency in intact mtDNA is not much higher than in the nuclear DNA, i.e., not more than a few modifications per million base pairs. Based on these data, it is hypothesized that the load of oxidative base modifications in mtDNA is efficiently reduced during replication even in the absence of excision repair.

Das folgende Kapitel richtet sich im Besonderen an Anwender, die Mobilitatsangebote fur die tagliche Praxis von Jugendlichen konzipieren, einfuhren und bewerten mussen. In U.Move ist diese Anwendungsperspektive durch die Verkehrsbetriebe Dortmund und Potsdam sowie durch die Deutsche Bahn vertreten worden. Um relevante Informationen fur die Angebotsseite zu erhalten, sind Teile der standardisierten Befragung und der vertiefenden Interviews auf regional- und anbieterspezifische Themen bezogen worden (z.B. Nutzung und Akzeptanz von mobilitatsbezogenen Informationsmedien oder von Event- und Nachtverkehrsangeboten). Die Analysen zu konkret existierenden oder geplanten Angeboten bieten vor dem Hintergrund der breiten Datenbasis der gesamten U.Move-Befragung und ihrer Typenbildung die Gelegenheit zu interessanten Quervergleichen und Erkenntnissen, die fur die kunftige Konzeption jugendspezifischer Mobilitatsangebote von einigem Nutzen sein konnen.

Background DNA is a carrier of biological information. The hybridization process, the formation of the DNA double-helix from single-strands with complementary sequences, is important for all living cells. DNA microarrays, among other biotechnologies such as PCR, rely on DNA hybridization. However, to date the thermodynamics of hybridization is only partly understood. Here we address, experimentally and theoretically, the hybridization of oligonucleotide strands of unequal lengths, which form a bulged loop upon hybridization. For our study we use in-house synthesized DNA microarrays. Results We synthesize a microarray with additional thymine bases in the probe sequence motifs so that bulged loops occur upon target hybridization. We observe a monotonic decrease of the fluorescence signal of the hybridized strands with increasing length of the bulged loop. This corresponds to a decrease in duplex binding affinity within the considered loop lengths of one to thirteen bases. By varying the position of the bulged loop along the DNA duplex, we observe a symmetric signal variation with respect to the center of the strand. We reproduce the experimental results well using a molecular zipper model at thermal equilibrium. However, binding states between both strands, which emerge through duplex opening at the position of the bulged loop, need to be taken into account. Conclusions We show that stable DNA duplexes with a bulged loop can form from short strands of unequal length and they contribute substantially to the fluorescence intensity from the hybridized strands on a microarray. In order to reproduce the result with the help of equilibrium thermodynamics, it is essential (and to a good approximation sufficient) to consider duplex opening not only at the ends but also at the position of the bulged loop. Although the thermodynamic parameters used in this study are taken from hybridization experiments in solution, these parameters fit our DNA microarray data well.