Midregional proatrial naturetic peptide (MRproANP) and copeptin (COPAVP) as predictors of all-cause mortality in recently diagnosed mild to moderate COPD-results from COSYCONET.

BACKGROUND: MRproANP and COPAVP are prognostic markers for mortality in chronic obstructive pulmonary disease (COPD). Furthermore, these biomarkers predict mortality due to cardiovascular diseases, which are important prognostically determining comorbidities in patients with COPD. However, less is known about these biomarkers in recently diagnosed mild to moderate COPD. Therefore, we analyzed these biomarkers as potential predictors of mortality in recently diagnosed mild to moderate COPD. METHODS: The blood biomarkers considered were copeptin (COPAVP), midregional adrenomedullin (MRproADM), midregional proatrial naturetic peptide (MRproANP), and fibrinogen. Analyses were performed in patients with stable "recently diagnosed mild to moderate COPD" defined by GOLD grades 0-2 and diagnosis of COPD ≤ 5 years prior to inclusion into the COSYCONET cohort (COPD and Systemic Consequences-Comorbidities Network), using Cox regression analysis with stepwise adjustment for multiple COPD characteristics, comorbidities, troponin and NT-proBNP. RESULTS: 655 patients with recently diagnosed mild to moderate COPD were included. In the initial regression model, 43 of 655 patients died during the 6-year follow-up, in the final model 27 of 487. Regression analyses with adjustment for confounders identified COPAVP and MRproANP as statistically robust biomarkers (p < 0.05 each) of all-cause mortality, while MRproADM and fibrinogen were not. The fourth quartile of MRproANP (97 pmol/L) was associated with a hazard ratio of 4.5 (95%CI: 1.6; 12.8), and the fourth quartile of COPAVP (9.2 pmol/L) with 3.0 (1.1; 8.0). The results for MRproANP were confirmed in the total cohort of grade 0-4 (n = 1470 finally). CONCLUSION: In patients with recently diagnosed mild to moderate COPD, elevated values of COPVP and in particular MRproANP were robust, independent biomarkers for all-cause mortality risk after adjustment for multiple other factors. This suggests that these markers might be considered in the risk assessment of early COPD.

Association between probable REM sleep behavior disorder and increased dermal alpha-synuclein deposition in Parkinson's disease.

INTRODUCTION: Many patients with Parkinson's disease suffer from REM sleep behavior disorder, potentially preceding the onset of motor symptoms. Phospho-alpha-synuclein is detectable in skin biopsies of patients with isolated REM sleep behavior disorder several years prior to the onset of manifest PD, but information on the association between dermal phospho-alpha-synuclein deposition and REM sleep behavior disorder in patients with manifest PD is limited. We therefore aimed to investigate the alpha-synuclein burden in dermal peripheral nerve fibers in patients with Parkinson's disease with and without REM sleep behavior disorder. METHODS: Patients with Parkinson's disease (n = 43) who had undergone skin biopsy for the immunohistochemical detection of phosphorylated alpha-synuclein were screened for REM sleep behavior disorder using RBDSQ and Mayo Sleep Questionnaire. Skin biopsies from 43 patients with isolated polysomnography-confirmed REM sleep behavior disorder were used as comparators. RESULTS: Dermal alpha-synuclein deposition was more frequently found (81.8% vs. 52.4%, p = 0.05) and was more abundant (p = 0.01) in patients with Parkinson's disease suffering from probable REM sleep behavior disorder compared to patients without REM sleep behavior disorder and was similar to patients with isolated REM sleep behavior disorder (79.1%). CONCLUSION: The phenotype of REM sleep behavior disorder is associated with high amounts of dermal alpha-synuclein deposition, demonstrating a strong involvement of peripheral nerves in patients with this non-motor symptom and may argue in favor of REM sleep behavior disorder as an indicator of a "body-predominant" subtype of Parkinson's disease.

Volatile fatty acid platform - a cornerstone for the circular bioeconomy.

Annually, the EU produces more than 100 million tonnes of urban biowaste, which is largely under-valorized and in some cases even still landfilled without any energy or material recovery. If Europe wants to be ready for the future, it will need to make better use of this large biomass potential within a circular economy approach. The research project funded by the European Commission under the Horizon 2020 programme entitled 'VOLATILE-Biowaste derived volatile fatty acid platform for biopolymers, bioactive compounds and chemical building blocks' aimed to produce volatile fatty acids (VFAs) from biowaste for reprocessing into products, materials or substances to close the material loop. During the project, the partners were able to obtain average volatile fatty acid yields of 627 g COD/kg organic matter (OM) for food waste, 448 g COD/kg OM for separately collected vegetable, garden and fruit waste (VGF) and 384 g COD/kg OM for the organic fraction of municipal solid waste (OF-MSW) at concentrations ranging from 12 to 48 g/L, 6 to 40 g/L and 13 to 26 g/L, respectively. A membrane filtration cascade consisting of micro-, ultra- and nano-filtration followed by reverse osmosis was identified as a feasible way to purify and concentrate the VFA effluent, making them a suitable carbon source for further fermentation processes. Besides technical optimization, socio-economic and legal aspects associated with this platform technology were also studied and show that although this technology is still in development, it is providing an answer to changing societal and market expectations both regarding organic waste treatment and bio-based production strategies. Based on the current technological, economic and market evolutions, it is expected that the VFAP will play an important role in organic waste treatment in the coming years.

T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. PATIENTS AND METHODS: We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed. RESULTS: HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. CONCLUSION: TCB should be developed in BC to circumvent low MHC/peptide complexes.

Detection of invasive pulmonary aspergillosis in critically ill patients by combined use of conventional culture, galactomannan, 1-3-beta-D-glucan and Aspergillus specific nested polymerase chain reaction in a prospective pilot study.

Invasive pulmonary aspergillosis (IPA) is an emerging and life-threatening infectious disease in patients admitted to the intensive care unit (ICU). Most diagnostic studies are conducted in hematological patients and results cannot readily be transferred to ICU patients lacking classical host factors. In a multicenter, prospective clinical trial including 44 ICU patients, hematological (n = 14) and non-hematological patients (n = 30), concurrent serum and bronchoalveolar lavage (BAL) samples were analyzed by conventional culture, galactomannan (GM), 1-3-beta-D-glucan (BDG) as well as an Aspergillus specific nested polymerase chain reaction (PCR). Nine patients (20%) had putative IPA according to AspICU classification. GM and PCR showed superior performance in BAL with sensitivity/specificity of 56%/94% and 44%/94% compared to 33%/97% and 11%/94% in serum. Despite better sensitivity of 89%, BDG showed poor specificity of only 31% (BAL) and 26% (serum). Combination of GM and PCR (BAL) with BDG (serum) resulted in 100% sensitivity, but also reduced specificity to 23%. Whereas mean GM levels were significantly higher in hematological patients BDG and PCR did not differ between hematological and non-hematological patients. Under present clinical conditions test combinations integrating both BAL and blood samples are advantageous. BDG might best serve as possible indicator for ruling out IPA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01695499. First posted: September 28, 2012, last update posted: May 8, 2017.

Dynamic Surface Enrichment in Drying Thin-Film Binary Polymer Solutions.

Solution-cast, thin-film polymer composites find a wide range of applications, such as in the photoactive layer of organic solar cells. The performance of this layer crucially relies on its phase-separated morphology. Efficient charge-carrier extraction requires each of the components to preferentially wet one of the two electrodes. It is often presumed that the experimentally observed surface enrichment required for this is caused by specific interactions of the active ingredients with each surface. By applying a generalized diffusion model, we find the dynamics to also play an important role in determining which component accumulates at which surface. We show that for sufficiently fast evaporation the component with the smallest cooperative diffusivity accumulates at the free interface. Counterintuitively, depending on the interactions between the various components, this may be the smaller solute. Our comprehensive numerical and analytical study provides a tool to predict and control phase-separated morphologies in thin-film polymer composites.

Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC).

Background: Lymphocytic infiltration at diagnosis is prognostic in EOC, however, the impact of NACT on tumour infiltrating lymphocytes (TILs) or PD-L1 expression remains poorly described. Patients and methods: Patients with EOC and sequential samples (pre-NACT, post-NACT or relapse) were retrospectively identified. TILs were evaluated on whole sections; stromal TILs (sTILs) scored as percentage of stromal area with high sTILs defined as ≥50%; intra-epithelial TILs (ieTILs) scored semi-quantitatively (0-3) with high ieTILs ≥2. A smaller number were available for PD-L1 evaluation, cut-off for positivity was ≥5% staining. Results: sTILs were detected in all tumours at diagnosis (range 2-90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired pre/post-NACT samples (N = 83), an overall increase in median sTILs from 20% to 30% was seen following NACT (P = 0.0005); individually the impact of NACT varied with sTILs increasing in 51% (42/83), decreasing in 25%, and stable in 24%. Post-NACT sTILs were predictive of platinum-free interval (PFI), patients with PFI ≥6 months had significantly higher post-NACT sTILs (sTILs 28% versus 18% for PFI <6 months, P = 0.026); pre-NACT sTILS were not predictive. At diagnosis, 23% showed high ieTILs, and following NACT 33% showed increasing ieTILs. Proportion of tumours with PD-L1-positive immune cells was 30% (15/50) pre-NACT and 53% (27/51) post-NACT (P = 0.026). Among paired tumours, 63% of PD-L1-negative tumours became positive after NACT, furthermore cisplatin induced PD-L1 expression in PD-L1-negative EOC cell lines. On multivariate analysis, high sTILs both pre- and post-NACT were independent prognostic factors for progression-free survival (PFS) (HR 0.49, P = 0.02 and HR 0.60, P = 0.05, respectively). No prognostic impact of ieTILs or PD-L1 expression was detected. Conclusions: In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.

Comparison of bioreactance non-invasive cardiac output measurements with cardiac magnetic resonance imaging.

Impedance cardiography measurement of cardiac output gained wide interest due to its ease of use and non-invasiveness. However, validation studies of different algorithms yielded diverging results. Bioreactance (BR) as a recent adaption differs fundamentally as the flow signal is derived from phase shifts. Our aim was to assess the accuracy and reproducibility of BR, as compared to the non-invasive gold standard--cardiac magnetic resonance imaging (CMR). We prospectively included 32 stable patients. BR was performed twice in the supine position and averaged over 30 seconds. Mean bias was 0.2 ± 1.8 l/minute (1 ± 28%, percentage error 55%) with limits of agreement ranging from  -3.4 to 3.7 l/minute. Reproducibility was acceptable with a mean bias of 0.1 ± 0.9 l/minute (1 ± 14%, 27%). Low cardiac output was significantly overestimated (-1.1 ± 1.5 l/minute), while high cardiac output was underestimated (1.5 ± 1.7 l/minute), (P=0.001), although reproducibility was unaffected. Bias and weight were moderately correlated in men (r = 0.50, P=0.02). No differences for accuracy were found in nine patients who had an arrhythmia (0.3 ± 1.4 versus 0.1 ± 2.0 l/minute, P=0.76), while clinically relevant differences were found in patients with mild aortic valve disease (1.9 ± 2.2 versus -0.3 ± 1.7 l/minute, P=0.02). Overall, BR showed insufficient agreement with CMR, overestimating low and underestimating high cardiac output states. Reproducibility was acceptable and not negatively affected by the circulatory condition. Consequently, absolute values acquired with BR should be interpreted with caution and must not be used interchangeably in clinical practice.

Ivy leaves dry extract EA 575® decreases LPS-induced IL-6 release from murine macrophages.

IL-6 plays a key role in the course of inflammatory processes as well as in the regulation of immune responses by the release of different cytokines. IL-6 is produced e.g. by macrophages recruited to the airways in response to a variety of inflammatory stimuli like allergens and respiratory viruses. Patients with inflammatory airway diseases therefore may benefit from therapies targeting the IL-6 pathway, e.g. reduction of the IL-6 release. Within this context, we tested the influence of the ivy leaves dry extract EA 575® on the LPS-induced release of IL-6 from murine macrophages (J774.2). One point seven µg/ml (5 µM) corticosterone served as positive control and was able to reduce LPS-induced IL-6 release by 46 ± 4%. EA 575® was tested in concentrations between 40 and 400 µg/ml. EA 575® decreased the LPS-induced IL-6 release in a dose-dependent manner and statistically significant by 25 ± 4%, 32 ± 4%, and 40 ± 7% in concentrations of 80, 160, and 400 µg/ml, respectively. The present data suggest an anti-inflammatory effect of EA 575® used in therapy of chronic- and acute inflammatory airway diseases accompanied with cough.

Elimination of charge carrier trapping in diluted semiconductors.

In 1962, Mark and Helfrich demonstrated that the current in a semiconductor containing traps is reduced by N/Nt(r), with N the amount of transport sites, Nt the amount of traps and r a number that depends on the trap energy distribution. For r > 1, the possibility opens that trapping effects can be nearly eliminated when N and Nt are simultaneously reduced. Solution-processed conjugated polymers are an excellent model system to test this hypothesis, because they can be easily diluted by blending them with a high-bandgap semiconductor. We demonstrate that in conjugated polymer blends with 10% active semiconductor and 90% high-bandgap host, the typical strong electron trapping can be effectively eliminated. As a result we were able to fabricate polymer light-emitting diodes with balanced electron and hole transport and reduced non-radiative trap-assisted recombination, leading to a doubling of their efficiency at nearly ten times lower material costs.

Diffuse Lipomatosis of the Thyroid Gland: Report of Two Cases and Review of The Literature of a Curious Entity

Aim: Study of the incidence of diffuse lipomatous infiltration of the thyroid gland. Patients and methods: 320 cases of thyroid pathology representing one year of activity of the pathology department; were reviewed by the authors. Results: We observed 2 cases of lipomatous infiltration of the thyroid gland; the princeps case showed mature adipose tissue scattered between the thyroid follicles; occupying approximately 40% of the thyroid gland; and only one other case upon review of the 320 thyroid glands registered in our pathology department this year; with about 5 to 10% of adipose tissue. We found randomly distributed adipocytes in subcapsular location in 59 cases (18.5%); with 24 cases (7.5 %) with more than 1% and 35 cases (11%) with less than 1% of adipocytes. We noticed also the presence of one adenolipoma

Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer.

BACKGROUND: Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC. PATIENTS AND METHODS: We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC. RESULTS: Intratumoral high levels (above median) of PAR (but not PARP1 protein levels) had a negative prognostic impact in both the training (92 stage I subjects) and validation (133 stage I and II subjects) cohorts, as determined by univariate and multivariate analyses. The simultaneous assessment of PAR and PDXK protein levels improved risk stratification. CONCLUSION: NSCLC patients with high intratumoral PARP1 activity (i.e. elevated PAR levels above median) and low PDXK expression (below median) had a dismal prognosis, while patients with low PARP1 activity and high PDXK expression had a favorable outcome. Altogether, these results underscore the clinical potential and possible therapeutic relevance of these biomarkers.

Structuring of polymer solutions upon solvent evaporation.

The morphology of solution-cast, phase-separated polymers becomes finer with increasing solvent evaporation rate. We address this observation theoretically for a model polymer where demixing is induced by steady solvent evaporation. In contrast to what is the case for a classical, thermal quench involving immiscible blends, the spinodal instability initially develops slowly and the associated length scale is not time invariant but decreases with time as t(-1/2). After a time lag, phase separation accelerates. Time lag and characteristic length exhibit power-law behavior as a function of the evaporation rate with exponents of -2/3 and -1/6. Interestingly, at later stages the spinodal structure disappears completely while a second length scale develops. The associated structure coarsens but does not follow the usual Lifshitz-Slyozov-Wagner kinetics.

Systems biology of cisplatin resistance: past, present and future.

The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.

Predictive biomarkers for cancer therapy with PARP inhibitors.

Poly(ADP-ribose) polymerase (PARP) inhibitors have raised high expectations for the treatment of multiple malignancies. PARP inhibitors, which can be used as monotherapies or in combination with DNA-damaging agents, are particularly efficient against tumors with defects in DNA repair mechanisms, in particular the homologous recombination pathway, for instance due to BRCA mutations. Thus, deficient DNA repair provides a framework for the success of PARP inhibitors in medical oncology. Here, we review encouraging results obtained in recent clinical trials investigating the safety and efficacy of PARP inhibitors as anticancer agents. We discuss emerging mechanisms of regulation of homologous recombination and how inhibition of DNA repair might be used in cancer therapy. We surmise that the identification of patients that are likely to benefit from PARP inhibition will improve the clinical use of PARP inhibitors in a defined target population. Thus, we will place special emphasis on biomarker discovery.

Molecular depth profiling of organic photovoltaic heterojunction layers by ToF-SIMS: comparative evaluation of three sputtering beams.

With the recent developments in secondary ion mass spectrometry (SIMS), it is now possible to obtain molecular depth profiles and 3D molecular images of organic thin films, i.e. SIMS depth profiles where the molecular information of the mass spectrum is retained through the sputtering of the sample. Several approaches have been proposed for "damageless" profiling, including the sputtering with SF5(+) and C60(+) clusters, low energy Cs(+) ions and, more recently, large noble gas clusters (Ar500-5000(+)). In this article, we evaluate the merits of these different approaches for the in depth analysis of organic photovoltaic heterojunctions involving poly(3-hexylthiophene) (P3HT) as the electron donor and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) as the acceptor. It is demonstrated that the use of 30 keV C60(3+) and 500 eV Cs(+) (500 eV per atom) leads to strong artifacts for layers in which the fullerene derivative PCBM is involved, related to crosslinking and topography development. In comparison, the profiles obtained using 10 keV Ar1700(+) (∼6 eV per atom) do not indicate any sign of artifacts and reveal fine compositional details in the blends. However, increasing the energy of the Ar cluster beam beyond that value leads to irreversible damage and failure of the molecular depth profiling. The profile qualities, apparent interface widths and sputtering yields are analyzed in detail. On the grounds of these experiments and recent molecular dynamics simulations, the discussion addresses the issues of damage and crater formation induced by the sputtering and the analysis ions in such radiation-sensitive materials, and their effects on the profile quality and the depth resolution. Solutions are proposed to optimize the depth resolution using either large Ar clusters or low energy cesium projectiles for sputtering and/or analysis.

Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses.

Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.

Detailed three-dimensional visualization of resilin in the exoskeleton of arthropods using confocal laser scanning microscopy.

Resilin is a rubber-like protein found in the exoskeleton of arthropods. It often contributes large proportions to the material of certain structures in movement systems. Accordingly, the knowledge of the presence and distribution of resilin is essential for the understanding of the functional morphology of these systems. Because of its specific autofluorescence, resilin can be effectively visualized using fluorescence microscopy. However, the respective excitation maximum is in the UV range, which is not covered by the lasers available in most of the modern commercial confocal laser scanning microscopes. The goal of this study was to test the potential of confocal laser scanning microscopy (CLSM) in combination with a 405 nm laser to visualize and analyse the presence and distribution of resilin in arthropod exoskeletons. The results clearly show that all resilin-dominated structures, which were visualized successfully using wide-field fluorescence microscopy (WFM) and a 'classical' UV excitation, could also be visualized efficiently with the proposed CLSM method. Furthermore, with the application of additional laser lines CLSM turned out to be very appropriate for studying differences in the material composition within arthropod exoskeletons in great detail. As CLSM has several advantages over WFM with respect to detailed morphological imaging, the application of the proposed CLSM method may reveal new information about the micromorphology and material composition of resilin-dominated exoskeleton structures leading to new insights into the functional morphology and biomechanics of arthropods.

Molecular mechanisms of cisplatin resistance.

Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNA-cisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.