Miracle-dz/UniFAR-FTUs huggingface dataset:
Cancer Therapy : Preclinical Ang-2-VEGF-A CrossMab , a Novel Bispeci fi c Human IgG 1 Antibody Blocking VEGF-A and Ang-2 Functions Simultaneously , Mediates Potent Antitumor , Antiangiogenic , and Antimetastatic Ef fi cacy

Purpose:VEGF-A blockade has been clinically validated as a treatment for human cancers. Angiopoietin2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis. Experimental Design:We have applied the recently developed CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on bevacizumab (Avastin), and the other arm recognizing Ang-2 based on LC06, an Ang-2 selective human IgG1 antibody. The potency of Ang-2VEGF CrossMab was evaluated alone and in combination with chemotherapy using orthotopic and subcutaneous xenotransplantations, along with metastasis analysis by quantitative real-time Alu-PCR and ex vivo evaluation of vessels, hypoxia, proliferation, and apoptosis. The mechanism of action was further elucidated using Western blotting and ELISA assays. Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneicmouse tumors and patient or cell line-derived human tumor xenografts, especially at later stages of tumor development. Ang-2-VEGF-A CrossMab treatment led to a strong inhibition of angiogenesisandanenhancedvesselmaturationphenotype.Neoadjuvantcombinationwithchemotherapyresulted in complete tumor regression in primary tumor-bearing Ang-2-VEGF-A CrossMab-treatedmice. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiologic vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting. Conclusion: These data establish Ang-2-VEGF-A CrossMab as a promising antitumor, antiangiogenic, and antimetastatic agent for the treatment of cancer. Clin Cancer Res; 19(24); 1–11. 2013 AACR.
Noninvasive ventilation strategy for weaning from mechanical ventilation for underlying COPD: How to get to be great being little?

Lung India • Vol 32 • Issue 1 • JanFeb 2015 than the controls, who were weaned using invasive PS weaning. It is possible that the benefits demonstrated by the authors are a reflection of the impact of reducing the incidence of VAP rather than benefits of NIV per se. It has been suggested from previous studies that the mortality benefits of using NIV in immunocompromised patients are mainly due to a reduction of the risks of developing VAP,[4] and perhaps we are just seeing another example of this effect in patients with COPD. The high mortality rate seen in the control group may also be a reflection of the incidence and impact of VAP in ventilated COPD patients.
Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases.

The balance between levels of metalloproteinases and their corresponding inhibitors is a critical factor in tumor invasion and metastasis. Down-regulation of the activity of these proteases was achieved by transfection of invasive and metastatic rat cells with the complementary DNA for metalloproteinase inhibitor/tissue inhibitor of metalloproteinase 2 (MI/TIMP-2), a novel inhibitor of metalloproteinases recently described. (Y. A. DeClerck et al., J. Biol. Chem., 264: 17445-17453, 1989; W. G. Stetler-Stevenson et al., J. Biol. Chem., 264: 17374-17378, 1989). Secretion of functional MI/TIMP-2 protein in stably transfected cells resulted in a marked decrease in metalloproteinase activity. Partial suppression of the formation of lung colonies after i.v. injection in nude mice was observed in a transfected clone expressing high levels of MI/TIMP-2. Production of MI/TIMP-2 in four clones markedly reduced tumor growth rate in vivo after s.c. injection and completely suppressed local tissue invasion. Thus, down-regulation of metalloproteinase activity has a striking effect on local invasion and partially suppresses hematogenous metastasis.
Validacija instrumenta za mjerenje privrženosti u različitim vrstama bliskih odnosa: Modifikacija Brennanova Inventara iskustava u bliskim vezama

Cilj ovog istraživanja bila je modifikacija Inventara iskustava u bliskim odnosima Brennana i suradnika (1998) u instrument za mjerenje privrženosti u razlicitim vrstama bliskih odnosa. Instrument Brennana i sur. koristi se iskljucivo za mjerenje privrženosti u vezama s ljubavnim partnerima. Kako bismo ispitali privrženost i u drugim vrstama bliskih odnosa (prema prijateljima ili clanovima obitelji), primijenili smo ga s drugacijim uputama i uz izmjenu objekta privrženosti u samim tvrdnjama. Ispitivanje je provedeno u dva dijela: na osnovi rezultata u prvom dijelu istraživanja instrument je skracen, a u drugom dijelu istraživanja primijenjen je na novom uzorku ispitanika iz iste populacije. Ispitanici su bili studenti zavrsnih godista studija psihologije i Visoke policijske skole u Zagrebu, oba spola (N1=210 ; N2=150). Rezultati su pokazali da je moguce dobiti upola kraci instrument kojim se uklanja sadržajna redundantnost, a zadržavaju gotovo sve karakteristike originalnog instrumenta. Faktorska struktura skale je ostala ista, zadržana su dva faktora: anksioznost i izbjegavanje, na koje se raspoređuje po 9 odgovarajucih cestica. Nova, ekonomicnija skala nije izgubila na pouzdanosti. Primjena skracene skale na novom uzorku ispitanika potvrdila je ocekivane metrijske karakteristike instrumenta.
Finger wrinkling after immersion in water

cases, although in two female patients this was not obtained until necropsy. There were 19 female and two male patients, the mean age of presentation was 57 9 years, and seven patients (33%) were over the age of 65. These data reveal that in Tayside the annual incidence of primary biliary cirrhosis is 10-6 per million. On 31 December 1979 16 patients with the diagnosis were still alive, revealing the point prevalence as 40 2 per million. The incidence figure is almost twice that found by Dr Triger in Sheffield (5-8 per million), and by other workers in NE England (6-0 per million-as reported at the September meeting of the British Society of Gastroenterology by Hamlyn et al.). The lower value for point prevalence may indicate higher mortality in Tayside, although it is similar to the figure in the Newcastle upon Tyne study (47 per million). The weakness in the Tayside data is the paucity of information on the number of non-biopsied cases during the study period, and on the number of biopsied cases alive prior to 1975. An attempt is being made to rectify this problem at present, but it is unlikely that these gaps in information have distorted the annual incidence figures greatly or significantly altered the point prevalence as late as the end of 1979. W STUART HISLOP Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY
Emigrants and Exiles: Ireland and the Irish Exodus to North America.

From the 1660s to the early 1900s, no fewer than seven million people emigrated from Ireland to North America. This vast flow at once reflected and compelled enormous social changes on both sides of the Atlantic. In this book Miller chronicles the momentous causes of the Irish emigration and its far-reaching impact - on the people themselves, on the land they left behind, and on the new one they came to. Drawing on enormous original research, Miller focuses on the thought and behaviour of the "ordinary" Irish emigrants, Catholic and Protestant, as revealed in their personal letters, diaries, journals, and memoirs as well as in their songs, poems, and folklore. Monumental in scope, Emigrants and Exiles embraces all the successive waves of Irish emigration, illuminating their differences as well as their common bonds.
Robust biomarker identification for cancer diagnosis with ensemble feature selection methods

MOTIVATION Biomarker discovery is an important topic in biomedical applications of computational biology, including applications such as gene and SNP selection from high-dimensional data. Surprisingly, the stability with respect to sampling variation or robustness of such selection processes has received attention only recently. However, robustness of biomarkers is an important issue, as it may greatly influence subsequent biological validations. In addition, a more robust set of markers may strengthen the confidence of an expert in the results of a selection method. RESULTS Our first contribution is a general framework for the analysis of the robustness of a biomarker selection algorithm. Secondly, we conducted a large-scale analysis of the recently introduced concept of ensemble feature selection, where multiple feature selections are combined in order to increase the robustness of the final set of selected features. We focus on selection methods that are embedded in the estimation of support vector machines (SVMs). SVMs are powerful classification models that have shown state-of-the-art performance on several diagnosis and prognosis tasks on biological data. Their feature selection extensions also offered good results for gene selection tasks. We show that the robustness of SVMs for biomarker discovery can be substantially increased by using ensemble feature selection techniques, while at the same time improving upon classification performances. The proposed methodology is evaluated on four microarray datasets showing increases of up to almost 30% in robustness of the selected biomarkers, along with an improvement of approximately 15% in classification performance. The stability improvement with ensemble methods is particularly noticeable for small signature sizes (a few tens of genes), which is most relevant for the design of a diagnosis or prognosis model from a gene signature. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Sublethal effects of the beta‐blocker sotalol at environmentally relevant concentrations on the New Zealand mudsnail Potamopyrgus antipodarum

Monitoring sublethal effects of pharmaceuticals on nontarget species in aquatic environments has become an important topic in ecotoxicology, yet few studies have been conducted concerning the effects of beta‐blockers on aquatic organisms. The present study investigated the effects of the beta‐blocker sotalol (SOT) at 3 environmentally relevant concentrations on life‐history traits of the New Zealand mudsnail Potamopyrgus antipodarum. Based on the pharmacodynamic properties of SOT, the authors hypothesized reduced numbers of embryos in the brood pouches, decelerated growth of adult snails, and smaller size of neonates, but no effect on mortality rates of adults. Contrary to the hypothesis, the total number of embryos was significantly higher after 56 d of exposure at nominal concentrations of 0.05 µg/L and 1.0 µg/L by 107% and 73%, respectively. No differences in embryo numbers were observed at earlier time‐points. Therefore, the mode of action seems to be an extension of the reproductive period rather than an increase of the embryo production. Furthermore, our results indicate a hormetic dose–response relationship, because no effects were observed at the highest test‐concentration (6.5 µg/L). Mortality, growth of adult snails, and neonate sizes were not affected by the beta‐blocker. Given the strong influence on reproduction, the effects of sublethal concentrations of SOT and other beta‐blockers deserve better consideration in ecotoxicological risk assessment. Environ Toxicol Chem 2014;33:2510–2515. © 2014 SETAC
The time-course of morphological constraints: A study of plurals inside derived words

The avoidance of regular but not irregular plurals inside compounds (e.g., *rats eater vs. mice eater) has been one of the most widely studied morphological phenomena in the psycholinguistics literature. To examine whether the constraints that are responsible for this contrast have any general significance beyond compounding, we investigated derived word forms containing regular and irregular plurals in two experiments. Experiment 1 was an offline acceptability judgment task, and Experiment 2 measured eye movements during reading derived words containing regular and irregular plurals and uninflected base nouns. The results from both experiments show that the constraint against regular plurals inside compounds generalizes to derived words. We argue that this constraint cannot be reduced to phonological properties, but is instead morphological in nature. The eye-movement data provide detailed information on the time-course of processing derived word forms indicating that early stages of processing are affected by a general constraint that disallows inflected words from feeding derivational processes, and that the more specific constraint against regular plurals comes in at a subsequent later stage of processing. We argue that these results are consistent with stage-based models of language processing.
Hormonal contraception and incident HIV-1 infection: new insight and continuing challenges.

Understanding whether hormonal contraception increases the risk of incident HIV-1 infection among women is a critical public health issue. Hormonal contraception a novelty just four decades ago has become the norm in many countries because of its high efficacy and ease of use. Over 120 million women worldwide use hormonal contraception and its use especially depo-medroxyprogesterone acetate (DMPA) is increasing rapidly in many resource-limited settings. Effective contraception has a key role to play in reducing maternal and infant mortality (by spacing pregnancies) and in allowing women a measure of control over when and how often they become pregnant. At the same time the HIV/AIDS epidemic has reached crisis proportions in a number of sub-Saharan countries and calls for a rapid expansion of both prevention and treatment in resource-limited settings particularly among women of childbearing age. Despite the magnitude of the HIV/AIDS epidemic the level of condom use among married or cohabiting couples in countries classified by UNAIDS as experiencing a generalized HIV epidemic remains very low. Most women who do use contraception rely on oral contraceptives (OC) or injectable DMPA. (excerpt)
‘Let's see if you can see me': making connections with Google Earth™ in a preschool classroom

Bringing a social interaction approach to children's geographies to investigate how children accomplish place in everyday lives, we draw on ethnomethodological and conversation analytic approaches that recognize children's competence to manipulate their social and digital worlds. An investigation of preschool-aged children engaged with Google Earth™ shows how they both claimed and displayed technological understandings and practices such as manoeuvring the mouse and screen, and referenced place through relationships with local landmarks and familiar settings such as their school. At times, the children's competing agendas required orientation to each other's ideas, and shared negotiation to come to resolution. A focus on children's use of digital technologies as they make meaning of the world around them makes possible new understandings of place within the geographies of childhood and education.
Paramagnetic micro-particles as a tool for rapid quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma by UHPLC-MS/MS

Abstract Background: Assessment of the anticoagulant activity of direct oral anticoagulants (DOACs) is justified in special clinical situations. Here, we evaluated two independent extraction methods and developed a multi-analyte ultra-high performance liquid chromatography tandem mass (UHPLC-MS/MS) method for the quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma. Methods: Routine extraction based on protein precipitation with acetonitrile and subsequent centrifugation was compared to sample clean-up using commercial paramagnetic micro-particles and subsequent magnetic depletion. Stable isotope-labeled analogs of all analytes were employed as internal standards. The method was validated according to international guidelines in terms of linearity, precision, trueness, sensitivity, recovery and matrix effects. The performances of both extraction methods were assessed in clinical samples obtained from patients treated with either apixaban or rivaroxaban. Additionally, we report on a patient with nonadherence to rivaroxaban treatment and fulminant pulmonary embolism. Results: The method was linear from 2 to 500 ng/mL for all analytes, and quantification of DOACs was established within a run time of 2.0 min. Based on MS/MS analyte responses, relative matrix effects were better controlled for dabigatran after extraction with paramagnetic micro-particles. Internal standards fully compensated for recovery and matrix effects in all assays, yielding equivalent results for both methods. Apixaban and rivaroxaban concentrations determined in clinical samples after extraction with both methods were in good agreement (R2=0.990). Conclusions: A rapid and accurate multi-component UHPLC-MS/MS method for the quantification of four DOACs in human plasma was established. Paramagnetic micro-particles appear suitable for clean-up of plasma samples for LC-MS/MS-based therapeutic drug monitoring purposes.
Proapoptotic and pronecrosis effect of different truncated hepatitis C virus core proteins.

OBJECTIVE To study the roles of different truncated hepatitis C virus (HCV) core proteins (CORE) in the pathogenesis of HCV persistent infection and hepatocellular carcinoma (HCC) and to assess intracellular localization in transiently transfected cells. METHODS Seven truncated GFP (green fluorescent protein)-CORE fusion protein expression plasmids were constructed, which contained HCV CORE sequences derived from tumor tissues (BT) and non-tumor tissues (BNT) from one patient infected with HCV. Amino acid (aa) lengths were BT: 1-172 aa, 1-126 aa, 1-58 aa, 59-126 aa, 127-172 aa; BNT: 1-172 aa and C191: 1-172 aa respectively. Subcellular localization of CORE-GFP was analyzed by con-focal laser scanning microscope. Apoptosis and necrosis were quantified by flow cytometry. RESULTS Different truncated CORE-GFP localized mainly in the cytoplasm, but nuclear staining was also observed. HCV CORE could induce apoptosis and necrosis, and different truncated COREs could induce cell apoptosis and necrosis at different levels. Among the same length 1-172 aa of BT, BNT and C191, the cell apoptosis and necrosis percentage of BT is highest, and C191 is the lowest (BT>BNT>C191). To the different fragment COREs of BT, N-terminal of CORE induced apoptosis and necrosis higher, compared with that of C-terminal (1-172 aa>1-126 aa>1-58 aa>127-172 aa>59-126 aa). CONCLUSION These results suggest HCV CORE could induce apoptosis and necrosis of cells, which might play an important role in the pathogenesis of HCV persistent infection and HCC and the different CORE domains of different HCV quasi-species might have some difference in their pathogenesis.
Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor positive premenopausal breast cancer.

PURPOSE Although there is evidence for interaction between epidermal growth factor receptor (EGFR) and estrogen receptor (ER), it is still not clear how this affects response to endocrine therapies like tamoxifen. Here we assess the relationship between EGFR expression and tamoxifen response, with a new quantitative technology. PATIENTS AND METHODS A tissue microarray was constructed from breast cancer from a cohort of 564 patients enrolled in a randomized clinical trial for adjuvant tamoxifen treatment in early breast cancer, with a median follow-up of 14 years. EGFR expression was measured using automated quantitative analysis, a fluorescence-based method for quantitative analysis of in situ protein expression. RESULTS In ER-positive patients, tamoxifen-treated patients with low EGFR expression (n = 113) showed a significant effect by 2 years of adjuvant tamoxifen (P = .01), in contrast to no treatment effect in the EGFR-high group (n = 73, P = .69). The untreated group showed 49% v 57% 10-year recurrence-free survival for EGFR low versus high (P = .466) in the corresponding group of ER-positive patients. A significant beneficial effect of tamoxifen treatment was seen in the EGFR-low group (hazard ratio [HR] = 0.43 (95% CI, 0.22 to 0.84; P = .013) in contrast to no effect in the EGFR-high group (HR = 1.14; 95% CI, 0.59 to 2.22; P = .7) by using a Cox model. CONCLUSION This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.
Generation of Escherichia coli O9a Serotype, a Subtype of E. coli O9, by Transfer of the wb* Gene Cluster of Klebsiella O3 into E. colivia Recombination

ABSTRACT Genetic characterization of the wb* gene in a series ofEscherichia coli and Klebsiella strains possessing the mannose homopolymer as the O-specific polysaccharide was carried out. The partial nucleotide sequences and PCR-restriction fragment length polymorphism analysis suggested that E. coli serotype O9a, a subtype of E. coli O9, might have been generated by the insertion of theKlebsiella O3 wb* gene into a certainE. coli strain.
Paper-based versus computer-based records in the emergency department: Staff preferences, expectations, and concerns

Although the potential benefits of computer-based records have been identified in different areas of the healthcare environment, in many settings paper-based records and computer-based records are still used in parallel. In this article, emergency department (ED) staff perspectives about the use of paper- or computer-based records are presented. This was a qualitative study in which data were collected using in-depth semi-structured interviews with the ED staff. The interviews were transcribed verbatim and data were analysed using framework analysis. In total, 34 interviews were undertaken. The study identified a number of factors which might encourage or discourage the use of paper-based and computer-based records in the ED. Users also expressed their concerns and expectations. Although there is a tendency towards computerizing healthcare settings, user acceptance of technology should not be underestimated. To improve user acceptance, users’ concerns should be investigated and addressed appropriately.
Synaptic Conductance Estimates of the Connection Between Local Inhibitor Interneurons and Pyramidal Neurons in Layer 2/3 of a Cortical Column

Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude −0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3.