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PurposeThe apparent diffusion coefficient (ADC) is increasingly used to characterize breast cancer. The peritumor/tumor ADC ratio is suggested to be a reliable and generally applicable index. However, its overall prognostication value remains unclear. We aimed to evaluate the associations between the peritumor/tumor ADC ratio and histopathological biomarkers and published prognostic tools in patients with invasive breast cancer.Materials and methodsThis prospective study included 88 lesions (five bilateral) in 83 patients with primary invasive breast cancer who underwent preoperative 3.0-T magnetic resonance imaging. The lowest intratumoral mean ADC value on the slice with the largest tumor cross-sectional area was designated the tumor ADC, and the highest mean ADC value on the peritumoral breast parenchymal tissue adjacent to the tumor border was designated the peritumor ADC. The peritumor/tumor ADC ratio was then calculated. The tumor and peritumor ADC values and peritumor/tumor ADC ratios were compared with histopathological parameters using an unpaired t test, and their correlations with published prognostic tools were evaluated with Pearson's correlation coefficient.ResultsThe peritumor/tumor ADC ratio was significantly associated with tumor size (pConclusionThe peritumor/tumor ADC ratio was correlated with histopathological biomarkers in patients with invasive breast cancer, showed significant correlations with published prognostic indexes, and may provide an easily applicable imaging index for the preoperative prognostic evaluation of breast cancer.

Introduction Autoimmune reactions in Graves’ disease (GD) occur not only in the thyroid gland, but also in the orbital connective tissue, eyelids, extraocular muscles. The occurrence of orbitopathy in the course of GD is influenced by environmental factors, e.g. cigarette smoking. Objectives The aim of the study was to analyze the effect of cigarette smoking on the efficacy of activity of radioiodine(131I) therapy in patients with GD. We also studied the influence of cigarette smoking and the efficacy of prednisone prophylaxis on the risk of thyroid-associated ophthalmopathy (TAO) development after radioiodine therapy (RIT) during two years of follow-up. Patients and methods Medical records of hyperthyroid patients treated with radioiodine had been included. Patients were scheduled to visit outpatient clinics at baseline and 1, 3, 6, 9, 12, 18, and 24 months after RIT. Results The studied group consisted of 336 patients (274 women, 62 men) diagnosed with GD and treated with RIT; 130 patients received second therapeutic dose of 131I due to recurrent hyperthyroidism. Among all studied patients, 220 (65.5%) were smokers and 116 (34.5%) non-smokers. In the group of smokers 115 (52.2%) of patients received single RIT, 105 (47.8%) received second dose of RAI due to recurrent hyperthyroidism. In non-smokers 91 (78.6%) received single activity of RAI, while 25 (21.4%) patients required second RIT due to recurrent hyperthyroidism. The ophthalmic symptoms in the group of smokers after RIT were less frequent, if the patient received preventative treatment in the form of oral prednisone (P = 0.0088). Conclusions The results of our study suggest that cigarette smoking reduces the efficacy of treatment with 131I in patients with GD. The study also confirmed the effectiveness of steroid prophylaxis against TAO development or exacerbation after RIT.

Background Antiangiogenic therapy, although part of standard treatment in ovarian cancer, has variable efficacy. Furthermore, little is known about the prognostic biomarkers and factors influencing angiogenesis in cancer tissue. We evaluated the expression of angiopoietin-2 and two endothelial tyrosine kinase receptors, Tie-1 and Tie-2, and assessed their value in the prediction of survival in patients with malignant epithelial ovarian cancer. We also compared the expression of these factors between primary high grade serous tumors and their distant metastasis. Materials and methods We evaluated 86 women with primary epithelial ovarian cancer. Matched distal omental metastasis were investigated in 18.6% cases (N = 16). The expression levels of angiogenic factors were evaluated by immunohistochemistry in 306 specimens and by qRT-PCR in 111 samples. Results A high epithelial expression level of Tie-2 is a significant prognostic factor in primary high grade serous ovarian cancer. It predicted significantly shorter overall survival both in univariate (p Conclusions The angiogenic factor, angiopoietin-2, and its receptor Tie-2 seem to be significant prognostic factors in primary epithelial ovarian cancer. Their expression levels are also increased in metastatic lesions in comparison with primary tumors.

Glioblastoma multiforme (GBM) is the most common type of malignant gliomas, characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior. Disappointing results in the treatment of gliomas with surgery, radiation and chemotherapy have fueled a search for new therapeutic targets and treatment modalities. Here we report new approach towards RNA interference therapy of glioblastoma multiforme based on the magnetic nanoparticles delivery of the double-stranded RNA (dsRNA) with homological sequences to mRNA of tenascin-C (TN-C), named ATN-RNA. The obtained nanocomposite consisted of polyethyleneimine (PEI) coated magnetic nanoparticles conjugated to the dsRNA show high efficiency in ATN-RNA delivery, resulting not only in significant TN-C expression level suppressesion, but also impairing the tumor cells migration. Moreover, synthesized nanomaterials show high contrast properties in magnetic resonance imaging (MRI) and low cytotoxicity combining with lack of induction of interferon response. We believe that the present work is a successful combination of effective, functional, non-immunostimulatory dsRNA delivery system based on magnetic nanoparticles with high potential for further application in GBM therapy.

We present a 3D model of the four transmembrane (TM) helical regions of bilitranslocase (BTL), a structurally uncharacterized protein that transports organic anions across the cell membrane. The model was computed by considering helix-helix interactions as primary constraints, using Monte Carlo simulations. The interactions between the TM2 and TM3 segments have been confirmed by Förster resonance energy transfer (FRET) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy, increasing our confidence in the model. Several insights into the BTL transport mechanism were obtained by analyzing the model. For example, the observed cis-trans Leu-Pro peptide bond isomerization in the TM3 fragment may indicate a key conformational change during anion transport by BTL. Our structural model of BTL may facilitate further studies, including drug discovery.

Background Preterm infants are at high risk of developing respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI). This observational epidemiologic study evaluated RSV disease burden and risk factors for RSV-associated LRTI hospitalization in preterm infants 33 weeks+0 days to 35 weeks+6 days gestational age not receiving RSV prophylaxis. Methods Preterm infants ≤6 months of age during RSV season (1 October 2013–30 April 2014) were followed at 72 sites across 23 countries from September 2013–July 2014 (study period). RSV testing was performed according to local clinical practice. Factors related to RSV-associated hospitalization for LRTI were identified using multivariable logistic regression with backward selection. Results Of the 2390 evaluable infants, 204 and 127 were hospitalized for LRTI during the study period and RSV season, respectively. Among these subjects, 64/204 and 46/127, respectively, were hospitalized for confirmed RSV LRTI. Study period and RSV season normalized RSV hospitalization rates (per 100 infant years) were 4.1 and 6.1, respectively. Factors associated with an increased risk of RSV-related LRTI hospitalization in multivariable analyses were smoking of family members (P

The Bifibobacterium longum subsp. longum 35624™ strain (formerly named Bifidobacterium longum subsp. infantis) is a well described probiotic with clinical efficacy in Irritable Bowel Syndrome clinical trials and induces immunoregulatory effects in mice and in humans. This paper presents (a) the genome sequence of the organism allowing the assignment to its correct subspeciation longum; (b) a comparative genome assessment with other B. longum strains and (c) the molecular structure of the 35624 exopolysaccharide (EPS624). Comparative genome analysis of the 35624 strain with other B. longum strains determined that the sub-speciation of the strain is longum and revealed the presence of a 35624-specific gene cluster, predicted to encode the biosynthetic machinery for EPS624. Following isolation and acid treatment of the EPS, its chemical structure was determined using gas and liquid chromatography for sugar constituent and linkage analysis, electrospray and matrix assisted laser desorption ionization mass spectrometry for sequencing and NMR. The EPS consists of a branched hexasaccharide repeating unit containing two galactose and two glucose moieties, galacturonic acid and the unusual sugar 6-deoxy-L-talose. These data demonstrate that the B. longum 35624 strain has specific genetic features, one of which leads to the generation of a characteristic exopolysaccharide.

Micro-RNAs are small, noncoding RNAs that act as tumor suppressors or oncogenes. MiR-200c is a member of the miR-200 family; it is known to be dysregulated in invasive breast carcinoma. MiR-200c maintains the epithelial-mesenchymal transition and inhibits cell migration and invasion. Recent studies showed that miR-200c regulated steroid hormone receptors, estrogen receptors (ER), and progesterone receptors (PR). The present study aimed to detect miR-200c in 172 invasive breast carcinoma cases selected from a prospective cohort enrolled in Kuopio, Eastern Finland, between 1990 and 1995. MiR-200c expression was determined with relative q-PCR, and results were compared to clinicopathological variables and patient outcome. We found that PR status combined with miR-200c expression was a significant marker of outcome. High miR-200c expression was associated with reduced survival in PR-negative cases (n = 68); low miR-200c expression indicated reduced survival in PR-positive cases (n = 86) (Cox regression: P = 0.002, OR = 3.433; and P = 0.004, OR = 4.176, respectively). In PR-negative cases, high miR-200c expression was associated with shortened relapse-free survival (Cox regression: P = 0.001, OR = 3.613); increased local/distant recurrence (Logistic regression: P = 0.006, OR = 3.965); and more frequent distant metastasis (Logistic regression: P = 0.015, OR = 3.390). We also found that high grade and low stage tumors were positively correlated with high miR-200c expression (Logistic regression for high grade tumors: P = 0.002, OR = 2.791 and for high stage tumors: P = 0.035, OR = 0.285). Our results indicated that miR-200c may play a role in invasive breast carcinoma. Furthermore, miR-200c combined with PR status provided a refined predictor of outcome. In future, a larger study is required to confirm our results. This data may provide a basis for new research target-progesterone receptor-regulated microRNAs in breast cancer.

Type II transmembrane serine proteases (TTSPs) are related to tumor growth, invasion, and metastasis in cancer. Genetic variants in these genes may alter their function, leading to cancer onset and progression, and affect patient outcome. Here, 464 breast cancer cases and 370 controls were genotyped for 82 single-nucleotide polymorphisms covering eight genes. Association of the genotypes was estimated against breast cancer risk, breast cancer–specific survival, and survival in different treatment groups, and clinicopathological variables. SNPs in TMPRSS3 (rs3814903 and rs11203200), TMPRSS7 (rs1844925), and HGF (rs5745752) associated significantly with breast cancer risk (P trend = 0.008–0.042). SNPs in TMPRSS1 (rs12151195 and rs12461158), TMPRSS2 (rs2276205), TMPRSS3 (rs3814903), and TMPRSS7 (rs2399403) associated with prognosis (P = 0.004–0.046). When estimating the combined effect of the variants, the risk of breast cancer was higher with 4–5 alleles present compared to 0–2 alleles (P = 0.0001; OR, 2.34; 95% CI, 1.39–3.94). Women with 6–8 survival-associating alleles had a 3.3 times higher risk of dying of breast cancer compared to women with 1–3 alleles (P = 0.001; HR, 3.30; 95% CI, 1.58–6.88). The results demonstrate the combined effect of variants in TTSPs and their related genes in breast cancer risk and patient outcome. Functional analysis of these variants will lead to further understanding of this gene family, which may improve individualized risk estimation and development of new strategies for treatment of breast cancer.

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95 confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95 CI: 0.95-0.99), rs10719 (OR 0.97; 95 Cl: 0.94-0.99), rs4687554 (OR 0.97; 95 CI: 0.95-0.99, and rs3134615 (OR 1.03; 95 CI: 1.01 -1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects. This is an open-access article free of all copyright.

Two β-galactosidases, β-gal I and β-gal II, from Bifidobacterium breve DSM 20213, which was isolated from the intestine of an infant, were overexpressed in Escherichia coli with co-expression of the chaperones GroEL/GroES, purified to electrophoretic homogeneity and biochemically characterized. Both β-gal I and β-gal II belong to glycoside hydrolase family 2 and are homodimers with native molecular masses of 220 and 211 kDa, respectively. The optimum pH and temperature for hydrolysis of the two substrates o-nitrophenyl-β-D-galactopyranoside (oNPG) and lactose were determined at pH 7.0 and 50°C for β-gal I, and at pH 6.5 and 55°C for β-gal II, respectively. The k cat/K m values for oNPG and lactose hydrolysis are 722 and 7.4 mM−1s−1 for β-gal I, and 543 and 25 mM−1s−1 for β-gal II. Both β-gal I and β-gal II are only moderately inhibited by their reaction products D-galactose and D-glucose. Both enzymes were found to be very well suited for the production of galacto-oligosaccharides with total GOS yields of 33% and 44% of total sugars obtained with β-gal I and β-gal II, respectively. The predominant transgalactosylation products are β-D-Galp-(1→6)-D-Glc (allolactose) and β-D-Galp-(1→3)-D-Lac, accounting together for more than 75% and 65% of the GOS formed by transgalactosylation by β-gal I and β-gal II, respectively, indicating that both enzymes have a propensity to synthesize β-(1→6) and β-(1→3)-linked GOS. The resulting GOS mixtures contained relatively high fractions of allolactose, which results from the fact that glucose is a far better acceptor for galactosyl transfer than galactose and lactose, and intramolecular transgalactosylation contributes significantly to the formation of this disaccharide.

BackgroundIchthyosauria is a diverse clade of marine amniotes that spanned most of the Mesozoic. Until recently, most authors interpreted the fossil record as showing that three major extinction events affected this group during its history: one during the latest Triassic, one at the Jurassic-Cretaceous boundary (JCB), and one (resulting in total extinction) at the Cenomanian-Turonian boundary. The JCB was believed to eradicate most of the peculiar morphotypes found in the Late Jurassic, in favor of apparently less specialized forms in the Cretaceous. However, the record of ichthyosaurs from the Berriasian-Barremian interval is extremely limited, and the effects of the end-Jurassic extinction event on ichthyosaurs remains poorly understood.Methodology/principal findingsBased on new material from the Hauterivian of England and Germany and on abundant material from the Cambridge Greensand Formation, we name a new ophthalmosaurid, Acamptonectes densus gen. et sp. nov. This taxon shares numerous features with Ophthalmosaurus, a genus now restricted to the Callovian-Berriasian interval. Our phylogenetic analysis indicates that Ophthalmosauridae diverged early in its history into two markedly distinct clades, Ophthalmosaurinae and Platypterygiinae, both of which cross the JCB and persist to the late Albian at least. To evaluate the effect of the JCB extinction event on ichthyosaurs, we calculated cladogenesis, extinction, and survival rates for each stage of the Oxfordian-Barremian interval, under different scenarios. The extinction rate during the JCB never surpasses the background extinction rate for the Oxfordian-Barremian interval and the JCB records one of the highest survival rates of the interval.Conclusions/significanceThere is currently no evidence that ichthyosaurs were affected by the JCB extinction event, in contrast to many other marine groups. Ophthalmosaurid ichthyosaurs remained diverse from their rapid radiation in the Middle Jurassic to their total extinction at the beginning of the Late Cretaceous.

BackgroundA new dinosaur tracksite from ?Middle Jurassic sediments of the Irhazer Group on the plains of Agadez (Rep. Niger, northwest Africa) revealed extraordinarily well preserved didactyl tracks of a digitigrade bipedal trackmaker. The distinct morphology of the pes imprints indicates a theropod trackmaker from a paravian maniraptoran closely related to birds.Methodology/principal findingsThe early age and the morphological traits of the tracks allow for description of the new ichnotaxon Paravipus didactyloides. A total of 120 tracks are assigned to 5 individual trackways. The 'medium-sized' tracks with an average footprint length of 27.5 cm and footprint width of 23.1 cm are deeply imprinted into the track bearing sandstone.Conclusions/significanceA comparison with other didactyl tracks gives new insights into the foot morphology of advanced maniraptoran theropods and contributes to knowledge of their evolutionary history. The new ichnotaxon takes an important position in the ichnological fossil record of Gondwana and the mid-Jurassic biota worldwide, because it is among the earliest known records of paravian maniraptorans and of didactyl theropod tracks from Africa.

γ-secretase is a large ubiquitously expressed protease complex composed of four core subunits: presenilin, Aph1, PEN-2, and nicastrin. The function of γ-secretase in the cells is to proteolytically cleave various proteins within their transmembrane domains. Presenilin and Aph1 occur as alternative variants belonging to mutually exclusive γ-secretase complexes and providing the complexes with heterogeneous biochemical and physiological properties. γ-secretase is proposed to have a role in the development and progression of cancer and γ-secretase inhibitors are intensively studied for their probable anti-tumor effects in various types of cancer models. Here, we for the first time determined mRNA expression levels of presenilin-1, presenilin-2, Aph1a, Aph1b, PEN-2, and nicastrin in a set of breast cancer tissue samples (N = 55) by quantitative real-time PCR in order to clarify the clinical significance of the expression of different γ-secretase complex components in breast cancer. We found a high positive correlation between the subunit expression levels implying a common regulation of transcription. Our univariate Kaplan-Meier survival analyses established low expression level of γ-secretase complex as a risk factor for breast cancer specific mortality. The tumors expressing low levels of γ-secretase complex were characterized by high histopathological tumor grade, low or no expression of estrogen and progesterone receptors and consequently high probability to fall into the class of triple negative breast cancer tumors. These results may provide novel tools to further categorize breast cancer tumors, especially the highly aggressive and poorly treatable breast cancer type of triple negative cases, and suggest a significant role for γ-secretase in breast cancer.

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6×10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8×10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2×10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8×10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8×10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3×10(-7), p(heterogeneity) = 5.1×10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours. ispartof: PLoS One vol:7 issue:8 ispartof: location:United States status: published

Background The early evolution of sauropod dinosaurs is poorly understood because of a highly incomplete fossil record. New discoveries of Early and Middle Jurassic sauropods have a great potential to lead to a better understanding of early sauropod evolution and to reevaluate the patterns of sauropod diversification. Principal Findings A new sauropod from the Middle Jurassic of Niger, Spinophorosaurus nigerensis n. gen. et sp., is the most complete basal sauropod currently known. The taxon shares many anatomical characters with Middle Jurassic East Asian sauropods, while it is strongly dissimilar to Lower and Middle Jurassic South American and Indian forms. A possible explanation for this pattern is a separation of Laurasian and South Gondwanan Middle Jurassic sauropod faunas by geographic barriers. Integration of phylogenetic analyses and paleogeographic data reveals congruence between early sauropod evolution and hypotheses about Jurassic paleoclimate and phytogeography. Conclusions Spinophorosaurus demonstrates that many putatively derived characters of Middle Jurassic East Asian sauropods are plesiomorphic for eusauropods, while South Gondwanan eusauropods may represent a specialized line. The anatomy of Spinophorosaurus indicates that key innovations in Jurassic sauropod evolution might have taken place in North Africa, an area close to the equator with summer-wet climate at that time. Jurassic climatic zones and phytogeography possibly controlled early sauropod diversification.