Po stopách evoluční historie a diverzity koloniálních zlativek

Současný stupeň poznání diverzity zlativek bohužel stále stojí převážně na tradičních popisech morfodruhů. Trvalým problémem pak je neexistence sekvenačních dat pro většinu těchto druhů. Z toho mimo jiné plyne, že po celém fylogenetickém stromu zlativek je rozptýleno několik běžných morfotypů (Ochromonas-like aj.). Je zřejmé, že aktuální taxonomie třídy a obsáhnutá diverzita rozhodně neodráží skutečné druhové bohatství zlativek. Navíc nedávné studie zaměřené na zlativky s křemičitými šupinami (Mallomonas, Paraphysomonas, Synura) jednoznačně ukázaly, že problematika (pseudo)kryptických druhů je běžným fenoménem i pro taxony s relativně dobrým konceptem (s využitím SEM/TEM ultrastruktury). Typická zlativka nicméně vypadá jako nahý bičíkovec, jehož jedinou pevnou strukturou v rámci životního cyklu je stomatocysta. Zatímco jednobuněční bičíkovci Ochromonas a Spumella byli nedávno podrobeni taxonomické revizi s využitím technik molekulární genetiky, koloniální bičíkovci s Uroglena-like morfotypem nikoliv. Hlavním cílem této práce proto bylo podrobit široce rozšířené koloniální zlativky s morfotypem Synura s.l. a Uroglena s.l., které způsobují nápadné sezónní populační boomy (vodní květy), moderní taxonomické revizi na základě znalosti jejich molekulární fylogeneze, morfologie/ultrastruktury a ekologie....Our current knowledge of chrysophyte diversity is still generally based on traditional morphospecies descriptions. Accordingly, sequence data exist for the minority of all described species. Consequently, several common morphotypes (e.g. Ochromonas-like flagellate) are scattered across the phylogenetic tree of Chrysophytes. It is evident that the postulated taxonomic diversity certainly does not reflect the real species richness in Chrysophytes. Moreover, recent studies on silica scaled chrysophytes (Mallomonas, Paraphysomonas, Synura) clearly demasked common problematics of (pseudo)cryptic species even within this group possessing relatively good species concept based on the ultrastructure of silica scales and bristles. Contrary, most of chrysophytes are naked flagellates forming stomatocysts as the only solid structure in their life cycles. While single-celled Ochromonas and Spumella were recently revisited using molecular genetic techniques, Uroglena-like colonials remained untreated. Therefore, the main objective of this thesis was to provide a modern taxonomic revision of the widespread colonial chrysophytes causing conspicuous seasonal massive population booms, Synura s.l. and Uroglena s.l., by a polyphasic approach encompassing molecular phylogeny, morphology/ultrastructure and ecology....Department of BotanyKatedra botanikyFaculty of SciencePřírodovědecká fakult

Far-infrared vibrational properties of linear C60 polymers: A comparison between neutral and charged materials

We report the far-infrared transmittance spectrum of a pure phase of the orthorhombic high-temperature and high-pressure C-60 polymer and compare the results with a previously published spectrum of the charged RbC60 orthorhombic polymer. Assignments for both spectra are made with the aid of first-principles quantum molecular dynamics simulations of the two materials. We find that the striking spectral differences between the neutral and charged linear fullerene polymers can be fully accounted for by charge effects on the C-60 ball

Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer

PurposeWe examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FAC×6 preoperative chemotherapy. We also performed an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms.Experimental Design273 patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n=138), or FAC × 6 (n=135) neoadjuvant chemotherapy. All patients underwent a pretreatment FNA biopsy of the tumor for gene expression profiling and treatment response prediction.ResultsThe pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (p<0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% (95%CI:21–56%), the negative predictive value (NPV) 88% (CI:77–95%) and the AUC 0.711. In the FAC arm, the PPV was 9% (CI:1–29%) and the AUC 0.584. This suggests that the genomic predictor may have regimen-specificity. Its performance was similar to a clinical variable-based predictor nomogram.ConclusionsGene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next generation predictive markers will need to be developed separately for different molecular subsets of breast cancers

Far-infrared vibrational properties of high-pressure-high-temperature C60 polymers and the C60 dimer

We report high-resolution far-infrared transmission measurements of the 2 + 2 cycloaddition C-60 dimer and two-dimensional rhombohedral and one-dimensional orthorhombic high-pressure high-temperature C60 polymers. In the spectral region investigated(20-650 cm(-1)), we see no low-energy interball modes, but symmetry breaking of the linked C-60 balls is evident in the complex spectrum of intramolecular modes. Experimental features suggest large splittings or frequency shifts of some IhC60-derived modes that are activated by symmetry reduction, implying that the balls are strongly distorted in these structures. We have calculated the vibrations of all three systems by first-principles quantum molecular dynamics and use them to assign the predominant IhC60 symmetries of observed modes. Pur calculations show unprecedentedly large downshifts of T-1u(2)-derived modes and extremely large splittings of other modes, both of which are consistent with the experimental spectra. For the rhombohedral and orthorhombic polymers, the T-1u(2)-derived mode that is polarized along the bonding direction is calculated to downshift below any T-1u(1)-derived modes. We also identify a previously unassigned feature near 610 cm(-1) in all three systems as a widely split or shifted mode derived from various silent IhC60 vibrations, confirming a strong perturbation model for these linked fullerene structures

The role of the systematic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: systematic review and meta analysis

Introduction: Cancer remains a leading cause of death worldwide. While a curative intent is the aim of any surgical treatment many patients either present with or go onto develop disseminated disease requiring systemic anti-cancer therapy with a palliative intent. Given their limited life expectancy appropriate allocation of treatment is vital. It is recognised that systemic chemoradiotherapy may shorten the quality/quantity of life in patients with advanced cancer. It is against this background that the present systematic review and meta-analysis of the prognostic value of markers of the systemic inflammatory response in patients with advanced cancer was conducted. Methods: An extensive literature review using targeted medical subject headings was carried out in the MEDLINE, EMBASE, and CDSR databases until the end of 2016. Titles were examined for relevance and studies relating to duplicate datasets, that were not published in English and that did not have full text availability were excluded. Full texts of relevant articles were obtained and were then examined to identify any further relevant articles. Results: The majority of studies were retrospective. The systemic inflammatory response, as evidenced by a number of markers at clinical thresholds, was reported to have independent prognostic value, across tumour types and geographical locations. In particular, C-reactive protein (CRP, 63 studies), albumin (33 studies) the Glasgow Prognostic Score (GPS, 44 studies) and the Neutrophil Lymphocyte Ratio (NLR, 59 articles) were consistently validated across tumour types and geographical locations. There was considerable variation in the thresholds reported to have prognostic value when CRP and albumin were examined. There was less variation in the thresholds reported for NLR and still less for the GPS. Discussion: The systemic inflammatory response, especially as evidenced by the GPS and NLR, has reliable prognostic value in patients with advanced cancer. Further prospective studies of their clinical utility in randomised clinical trials and in treatment allocation are warranted

Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

International audienceABSTRACT: INTRODUCTION: The PACS01 trial has demonstrated that docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel benefit. METHODS: Tumor samples from 1.099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested. RESULTS: Progesterone receptor-negativity (HR=0.66; 95%CI 0.47-0.92, P=0.013), and Ki67-positivity (HR=1.53; 95%CI 1.12-2.08, P=0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR=0.51, 95%CI 0.33-0.79 for Ki67-positive versus HR=1.10, 95%CI 0.75-1.61 for Ki67-negative tumors, P for interaction=0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR=1.16, 95%CI 0.73-1.84); the reduction in the relapse risk was 53% (HR=0.47, 95%CI 0.22-1.01), 34% (HR=0.66, 95%CI 0.37-1.19), and 12% (HR=0.88, 95%CI 0.49-1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively. CONCLUSIONS: In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Preclinical and post-treatment changes in the HCC-associated serum proteome

SELDI-based proteomic profiling of body fluids is currently in widespread use for cancer biomarker discovery. We have successfully used this technology for the diagnosis of hepatocellular carcinoma (HCC) in hepatitis C patients and now report its application to serial serum samples from 37 hepatitis C patients before development of HCC, with HCC and following radiofrequency ablation of the tumour. As with alpha-fetoprotein, an accepted biomarker for HCC, we hypothesised that HCC-associated proteomic features would ‘return to normal' following successful treatment and the primary aim of our study was to test this hypothesis. Several SELDI peaks that changed significantly during HCC development were detected but they did not reverse following treatment. These data may be interpreted to suggest that the characteristic SELDI profile is not linearly related to tumour burden but may result from the progression of underlying liver disease or from the emergence of precancerous lesions. β2-Microglobulin, a protein previously reported to be markedly elevated in patients with HCV related HCC, was also the most significantly HCC associated proteomic feature (m/z 11720) in this study

Triple negative breast cancer: proposals for a pragmatic definition and implications for patient management and trial design.

In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics