Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases

Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information

Quality of life in patients with limited (1-3) brain metastases undergoing stereotactic or whole brain radiotherapy

Purpose Published results of quality of life (QoL) studies mostly concern whole brain radiotherapy for limited or multiple brain metastases. This prospective multicentre study was designed to compare the QoL of patients with limited (1-3) brain metastases treated with either whole brain (WBRT) or stereotactic radiotherapy (SRT). Methods From 01/2007-03/2011, 90 limited brain metastases patients who were previously untreated (n= 77) or had undergone primary surgery (n= 13) were recruited at 14 centres in Germany and Austria. QoL was measured with the EORTC-QLQ-C15-PAL and BN20 brain modules before the start of radiotherapy and after 3 months. Results Fifty-two patients (58%) received WBRT and 38 (42%) received SRT. At 3 months, 67 patients (74%) were still living, and 92.6% of the 3-month survivors completed the second set of questionnaires. Analysis of the QLQ-C15-PAL and BN20 scales revealed significant deterioration in patients treated with WBRT and SRT in physical function (p< 0.001 and p= 0.007), fatigue (p< 0.001 and p= 0.036), nausea (p= 0.003 and p= 0.002), appetite loss (p< 0.001 and p= 0.025), drowsiness (p< 0.001 and p= 0.011), hair loss (p= 0.019 and p= 0.023) and itchy skin (p= 0.030 and p= 0.018). Motor dysfunction (p< 0.001), communication deficits (p= 0.002) and leg weakness (p< 0.001) declined significantly only in patients treated with WBRT. Comparing the two radiotherapy techniques over time, the results showed significant differences in symptom scores for future uncertainty, fatigue and appetite loss. Conclusions QoL data as an outcome of the paper should be considered in decision making on the irradiation technique in patients with small number of brain metastases. Larger studies are required to verify the results according to subgroups

A new look on the corrosion mechanism of magnesium: An EIS investigation at different pH

International audienceThis study investigates the electrochemical impedance diagrams obtained for a Mg electrode in a sodium sulphate solution at different pHs. A comprehensive model, independent of the pH range, with the presence of two adsorbed intermediates accounting for the anodic dissolution and the cathodic reaction was proposed to explain the singular behaviour of Mg at low pH values. It was also shown that, in acidic media, the contribution of the double layer as well as the cathodic partial reaction must be considered, whereas at higher pH values the oxide/hydroxide layer plays a significant role and slows down the magnesium corrosion rate

Myrtus communis leaf compounds as novel inhibitors of quorum sensing-regulated virulence factors and biofilm formation: In vitro and in silico investigations

Antibiotic resistance of the Gram-negative bacterium Pseudomonas aeruginosa and its ability to form biofilm through the Quorum Sensing (QS) mechanism are important challenges in the control of infections caused by this pathogen. The extract of Myrtus communis (myrtle) showed strong anti-QS effect on Chromobacterium. violaceum 6267 by inhibiting 80 % of the production of violacein pigment at a sub-MIC concentration of 1/8 (31.25 μg/mL). In addition, the extract exhibited an inhibitory effect on virulence factors of P. aeruginosa PAO1 at half MIC (125 μg/mL), significantly reducing the formation of biofilms (72.02 %), the swarming activity (75 %), and the production of protease (61.83 %) and pyocyanin (97 %). The active fraction also downregulated the expression of selected regulatory genes involved in the biofilm formation and QS in the P. aeruginosa PAO1 strain. These genes included the autoinducer synthase genes (lasI and rhlI), the genes involved in the expression of their corresponding receptors (lasR and rhlR), and the pqsA genes. The analysis of the active fraction by HPLC/UV/MS and NMR allowed the identification of three phenolic compounds, 3,5-di-O-galloylquinic acid, myricetin 3-O-α-l-rhamnopyranoside (myricitrin), and myricetin 3-O-(2″-O-galloyl)-ß-d-galactopyranoside. In silico studies showed that 3,5-di-O-galloylquinic acid, with an affinity score of −9.20 kcal/mol, had the highest affinity to the active site of the CviR protein (3QP8), a QS receptor from C. violaceum. Additionally, myricetin 3-O-α-l-rhamnopyranoside (myricitrin) and myricetin 3-O-(2″-O-galloyl)-ß-d-galactopyranoside interact to a lesser extent with 3QP8. In conclusion, this study contributed significantly to the discovery of new QS inhibitors from M. communis leaves against resistant Gram-negative pathogens

Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

Abstract Background Renal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors. Methods Using Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells. Results Here we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation. Conclusions Identification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies

Additional file 3: Figure S3. of Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

a Western blots were loaded with whole cell lysates of cultured human cells (RPE-1) that had been transfected either with scrambled control siRNA or with two different siRNAs targeting FLCN. Staining with the anti-FLCN antibody shows one specific band at the expected molecular weight the intensity of which is strongly reduced by FLCN knockdown (left panel). Anti-Actin staining of the same membrane was used to control for equal loading (right panel). b To check whether the antibody was suitable for IHC as well we stained cell pellets of the established FLCN knockout cell line UOK257 lentivirally transduced to express emGFP (left image) showing little to no signal. UOK257cells that had been lentivirally transduced to express FLCN show a strong signal (magnification 40×). c IHC in human tissue shows that FLCN can still be detected in the chromophobe renal cell carcinoma of the BHD patient (middle panel). Normal human kidney tissue from a control (left side) was stained for comparison and shows a stronger signal. A control staining without the FLCN first antibody is shown on the right side of the panel (magnification 40×). (PDF 9710 kb

Additional file 2: Figure S2. of Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer

Exon 10, intron 10 and exon 11 of FLCN were cloned into an expression vector. After transfection into mIMCD cells (of mouse origin) RNA and afterwards cDNA was prepared and subjected to sequencing and PCR. As expected in the wildtype (WT) situation, intron 10 (= 565 bp) is spliced out, resulting in a PCR product of 197 bp when using primers that are located in exon10 and exon11. The patient mutation leads to a not functional splice acceptor site in front of exon 11. As a consequence, intron 10 is not spliced out leading to larger PCR product of 762 bp. Human cDNA and human genomic DNA served as controls for the PCR products. Sanger sequencings confirmed the results, electropherograms of the crucial junctions are shown. (PDF 929 kb