Current Status of Intensified Neo-Adjuvant Systemic Therapy in Locally Advanced Rectal Cancer

The addition of 5-fluorouracil (5-FU) or its prodrug capecitabine to radiotherapy (RT) is a standard approach in the neo-adjuvant treatment of patients with rectal tumors extending beyond the muscularis propria (stage II) and/or with clinical evidence of regional lymph node metastases (stage III). According to European randomized trials, the combined treatment modality resulted in favorable local control rates as compared with radiotherapy (RT) alone, but no improvement was found regarding the occurrence of distant metastases or overall survival. In an effort to further enhance the response rates and to decrease the high incidence of distant metastases in locally advanced rectal cancer patients, the addition of other chemotherapeutical drugs and biologic agents as radiation sensitizers to neo-adjuvant 5-FU based chemoradiotherapy (CRT) has been recently investigated. The role of those agents is however questionable as first results from phase III data do not show improvement on pathologic complete remission and circumferential resection margin negative resection rates as compared to 5-FU based CRT, nevertheless an increased toxicity

Oxidation, Coordination, and Nickel-Mediated Deconstruction of a Highly Electron-Rich Diboron Analogue of 1,3,5-Hexatriene

The reductive coupling of an N-heterocyclic carbene (NHC) stabilized (dibromo)vinylborane yields a 1,2-divinyldiborene, which, although isoelectronic to a 1,3,5-triene, displays no extended π conjugation because of twisting of the C2B2C2 chain. While this divinyldiborene coordinates to copper(I) and platinum(0) in an η2-B2 and η4-C2B2 fashion, respectively, it undergoes a complex rearrangement to an η4-1,3-diborete upon complexation with nickel(0)

Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For inoperable patients, we evaluated in this study intensity-modulated and image-guided radiotherapy (IMRT-IGRT) by helical tomotherapy.</p> <p>Methods</p> <p>Twenty-four CRC patients with ≤ 5 metastases were enrolled, receiving a dose of 50 Gy in fractions of 5 Gy. No limitations concerning dimension or localization of the metastases were imposed. Whole body PET-CT was performed at baseline and 3 months after the initiation of RT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0.</p> <p>Results</p> <p>A total of 53 metastases were treated. Seventeen patients (71%) received previously ≥ 1 line of chemotherapy for metastatic disease, displaying residual (n = 7) or progressive (n = 10) metabolic active oligometastatic disease at time of inclusion. Most common sites were the lung, liver and lymphnodes. One patient (4%) experienced grade 3 dysphagia. Twenty-two patients were evaluated by post-treatment PET-CT. Twelve patients achieved a complete (n = 6) or partial (n = 6) metabolic response, resulting in an overall metabolic response rate of 55%. At a median follow-up of 10 months, 7 patients (29%) are in remission, of which 5 received previous chemotherapy with residual oligometastatic disease at time of inclusion. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 14% and 78%.</p> <p>Conclusions</p> <p>Helical tomotherapy delivering 10 fractions of 5 Gy resulted in a metabolic response rate of 55%, and appeared to be attractive as consolidation of inoperable oligometastatic disease after effective chemotherapy.</p> <p>Trial registration</p> <p>Eudract 2008-008300-40; <a href="http://www.clinicaltrials.gov/ct2/show/NCT00807313">NCT00807313</a></p

Ab initio Berechnung der (110) Oberfläche von III - V Halbleitern : Simulation von Rastertunnelmikroskopieaufnahmen

Verbindungshalbleiter sind vor allem wegen ihrer Verwendbarkeit in optoelektronischen Bauelementen von besonderem technologischen Interesse. Voraussetzung ftlr Herstellung und zielgerichtetes Design elektronischer Bauelemente ist ein genaues Verstandnis der atomaren und elektronischen Struktur von Halbleiter-Schichtsystemen und Oberflachen. Eines der wichtigsten experimentellen Werkzeuge fiir die Untersuchung von Oberflachen ist die Rastertunnelmikroskopie (RTM). Obwohl die RTM auf einzigartige Weise eine Abbildung der elektronischen Oberflachenstruktur mit atomarer Aufldsung ermoglicht, so kann sie doch dieatomare Oberflachengeometrie nicht immer direkt und zweifelsfrei klaren. Die hierzu fehlende Verbindung zwischen elektronischer Struktur (lokale Zustandsdichte) und atomarer Geometrie (Atompositionen) kann durch "ab initio"-Rechnungen hergestellt werde

Ab-initio-Berechnung der (110)-Oberfläche von III-V-Halbleitern : Simulation von Rastertunnelmikroskopie-Aufnahmen

Verbindungshalbleiter sind vor allem wegen ihrer Verwendbarkeit in optoelektronischen Bauelementen von besonderem technologischen Interesse. Voraussetzung ftlr Herstellung und zielgerichtetes Design elektronischer Bauelemente ist ein genaues Verstandnis der atomaren und elektronischen Struktur von Halbleiter-Schichtsystemen und Oberflachen. Eines der wichtigsten experimentellen Werkzeuge fiir die Untersuchung von Oberflachen ist die Rastertunnelmikroskopie (RTM). Obwohl die RTM auf einzigartige Weise eine Abbildung der elektronischen Oberflachenstruktur mit atomarer Aufldsung ermoglicht, so kann sie doch dieatomare Oberflachengeometrie nicht immer direkt und zweifelsfrei klaren. Die hierzu fehlende Verbindung zwischen elektronischer Struktur (lokale Zustandsdichte) und atomarer Geometrie (Atompositionen) kann durch "ab initio"-Rechnungen hergestellt werde

Untersuchungen zur Biosynthese sesquiterpenoider Naturstoffe, der Melleolide, in Armillaria gallica

The present work shows the study on the elucidation of the biosynthetic pathway to sesquiterpenoid hybrid natural products, armillylorsellinates and melleolides, the class of natural products with the highest described structural diversity and interesting antimicrobial and cytotoxic activity. Due to the high complexity and diversity of synthesized molecules and the lack of possibilities to manipulate the natural producers Armillaria sp., there is great interest in elucidation of the biosynthetic pathway. This consists of cloning and functional characterization of involved genes and enzymes. After the attempted isolation of the key enzyme, the terpene cyclase protoilludene synthase to identify a homogeneous protein fraction, identification and cloning of the gene was achieved by sequencing of 2592 cDNA sequences of Armillaria gallica FU02472 transcriptome. The enzyme activity characterization of the native enzyme from A. gallica FU02472 and the heterologous protein expressed in E. coli as 6-Protoilludensynthase was achieved by the establishment of a radioactive activity assay and radio-thin-layer chromatography as well as a non - radioactive assay and detection of the biocatalysis products by GC/MS. Determining the copy number of the terpene cyclase showed that it was a single copy in the genome. Screening of a genomic library led to the identification of a 22.9 kb DNA fragment. Sequencing and comparison with the NCBI BLAST database confirmed the expected clustered organization of genes presumably associated to the biosynthesis. The following identification of an adjacent genomic fragment allowed the identification of four cytochrome P450 monooxygenases and two reading frames with previously uncharacterized function in addition to the terpene cyclase. The cloning of the cDNA sequences and the analysis of genomic clones showed a very complex structure of the coding (exon) and noncoding (intron) sequences for all the considered genes. With an average intron length of ~ 50 bp, for example, an exon was identified consisting of only five base pairs. This complex structure led to the cloning of incorrectly processed cDNA sequences. After correction and putative functional cloning, the four cytochrome P450 monooxygenases were subjected to functional testing of candidates with tritium-labeled 6-protoilludene, the exclusive product of the enzymatic reaction of farnesyl diphosphate catalyzed by Protoilludene synthase. For this purpose, in vivo feeding experiments with Saccharomyces cerevisiae (S. cerevisiae) were carried out and demonstrated the activity of the enzyme CYP Arm3. The construction of a plasmid-based S. cerevisiae production strain by expression of the catalytic domain of the HMG-CoA reductase, for the partial decoupling of feedback regulation mechanisms of the mevalonate pathway, NADPH:cytochrome P450 reductase for the cofactor regenerating, the identified terpene cyclase protoilludene synthase and P450 monooxygenase CYP Arm3 allowed the heterologous production of a putative monohydroxylated sesquiterpene skeleton. By isolation of the metabolite from the solvent extract of cell mass and culture supernatant, the position of hydroxylation was determined by NMR analysis. Based on the identification of 8alpha-hydroxy-6- Protoilludene another intermediate the 8alpha ,13-hydroxy- Protoilluden was identified using the established system. Functional characterization and heterologous expression of the terpene synthase and of two P450 monooxygenases shows for the first time the production of dihydroxylated sesquiterpene from higher fungi, in particular from basidiomycetes. This observation indicates that the biosynthetic pathway branches after the formation of terpene skeleton 6-protoilludene to the formation of armillylorsellinates and melleolides. The modification in the protoilludene skeleton starts with hydroxylation of the six-membered ring and modifications. Finally the transfer of the side chain (orsellinic acid - polyketide), according to the putative biosynthetic pathway, is catalyzed. The engineered strain is a platform development for the production of highly modified protoilludene skeletons for chemical or enzymatic semisynthesis to generate armillylorsellinate or melleolide derivatives for enhanced antibiotic and cytotoxic activity testing. The successful development of pharmaceutically relevant metabolites has been shown for example for illudin analogues (cytostatics) and pseudomutilines (terpene-based antibiotics)