An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: gefitinib (Iressatrade mark)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review)

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have beenreported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a generalagreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstreamof EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However,there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKIefficacy. We recently monitored gene expression profiles andsub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin,epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cellsensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated(up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times)of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second,loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breastcancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells.In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene,oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 functionalso leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands,and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. Therelevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypassthe antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades

Transactional sex and HIV risks - evidence from a cross-sectional national survey among young people in Uganda.

BACKGROUND: Transactional sex is associated with the HIV epidemic among young people in Uganda. Few quantitative studies based on nationally representative survey data explored the relationship between sexual behaviors, HIV infection, and transactional sex. OBJECTIVE: This study aimed to determine the associations between risky sexual behaviors, participation in transactional sex, and HIV sero-status among men and women aged 15-24 in Uganda. DESIGN: The study uses data from the Uganda AIDS Indicator Survey, a cross-sectional national HIV serological study conducted in 2011. We analyzed data on 1,516 men and 2,824 women aged 15-24 who had been sexually active in the 12 months preceding the survey. Private, face-to-face interviews were also conducted to record the sociodemographics, sexual history, and experiences of sexual coercion. Logistic regression analysis was performed to measure associations between sexual behaviors and transactional sex, and associations between HIV sero-status and transactional sex. RESULTS: Among young people who had been sexually active in the 12 months prior to the survey, 5.2% of young men reported paying for sex while 3.7% of young women reported receiving gifts, favors, or money for sex. Lower educational attainment (ORadjusted 3.25, CI 1.10-9.60) and experience of sexual coercion (ORadjusted 2.83, CI 1.07-7.47) were significantly associated with paying for sex among men. Multiple concurrent sexual relationships were significantly associated with paying for sex among young men (ORadjusted 5.60, CI 2.08-14.95) and receiving something for sex among young women (ORadjusted 8.04, CI 2.55-25.37). Paying for sex among young men and having three to five lifetime sexual partners among young women were associated with increased odds of testing positive for HIV. CONCLUSIONS: Transactional sex is associated with sexual coercion and HIV risk behaviors such as multiple concurrent sexual partnerships among young people in Uganda. In addition, transactional sex appears to place young men at increased risk for HIV in Uganda. Both sexes appear equally vulnerable to risks associated with transactional sex, and therefore should be targeted in intervention programs. In addition, strengthening universal education policy and improving school retention programs may be beneficial in reducing risky sexual behaviors and transactional sex.

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data.

BACKGROUND: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. METHODS: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. FINDINGS: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). INTERPRETATION: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. FUNDING: Bill & Melinda Gates Foundation.

Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity

The ascending midbrain 5-HT neurons to the forebrain may be dysregulated in depression and have a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by coimmunoprecipitation and colocation of the FGFR1 and 5-HT1A immunoreactivities in the midbrain raphe cells, evidence for the existence of FGFR1-5-HT1A receptor heterocomplexes in the dorsal and median raphe nuclei of the Sprague Dawley rat as well as in the rat medullary raphe RN33B cells has been obtained. Especially after combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA clusters was found in the RN33B cells. Similar results were reached with the FRET technique in HEK293T cells, where TM-V of the 5HT1A receptor was found to be part of the receptor interface. The combined treatment with FGF-2 and the 5-HT1A agonist also synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and the RN33B cells as well as their differentiation, as seen from development of the increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TM-V but not by TM-II. Together, the results indicate that the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A receptor heterocomplex in the midbrain raphe 5-HT nerve cells appear to have a trophic role in the central 5-HT neuron systems in addition to playing a key role in reducing the firing of these neurons

The effects of inter-crop cultivation Between rows of citrus crop on spreading of Guignardia citricarpa Ascospores and in the citrus black spot occurrence

This study highlighted the effect of planting coast-cross grass and forage peanut cv. Amarilis between rows of Natal oranges on spreading of Guignardia citricarpa ascospores and consequent citrus black spot control. Treatments evaluated were: 1- conventional cultivation, free of fungicides; 2- conventional cultivation, using protective fungicides; 3- inter-crop cultivation of coast-cross grass between rows of citrus crops and; 4- inter-cropping cultivation of forage peanut between the rows of citrus crops. Quest Volumetric Spore SystemTM traps were set in order to determine the number of ascospores released. A total of 33 inspections were conducted weekly, from the end of August until early September the following year. A diagrammatic scale was used to determine the severity of the disease as well as the percentage of fruits having a commercial standard. The coast-cross grass was more effective in reducing the number of ascospores produced, whose average statistics were lower than in the conventional treatments, free-fungicides. The inter-crop and conventional cultivation method coupled with fungicide treatment was more effective in reducing the severity of citrus black spot symptoms, and differs statistically from the fungicide-free control method. These methods also resulted in a higher percentage of fruits of a commercial standard, ranging from the 89% through the 91% percentile, and the cultivation, free of fungicides, fell within the 73%.

Antihypertensive Combination Treatment: State of the Art.

An adequate control of blood pressure is essential to reduce the risk of target organ damages and cardiovascular events in patients with hypertension. Yet, it is well recognized that a substantial proportion of treated patients remain hypertensive despite treatment. Several reasons have been evoked to explain why so many patients are not adequately controlled. Among them, medical inertia, a poor long-term adherence, and the need to prescribe several antihypertensive drugs to reach the target blood pressure have been identified as major limitations to the success of antihypertensive therapy. In this context, the use of single-pill combinations (SPC) containing two or three drugs in one pill has an important role in reducing the impact of some of these issues. Indeed, the use of SPC enables to reduce the pill burden and to improve the treatment efficacy without increasing the incidence of side effects. However, besides their major advantages, SPC have also some limitations such as a possible lack of flexibility or a higher cost. The purpose of this review is to discuss the place of SPC in the actual management of hypertension. The active development of new single-pill combinations in last years can be considered as a significant improvement in the physicians' capacity to treat hypertension effectively.

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Efectividad de la intervención psicosocial en pacientes con enfermedad avanzada y final de vida

Objetivos: Demostrar la efectividad de la intervención psicosocial en la atención integral a personas con enfermedades avanzadas. Método: Se ha evaluado la presencia y evolución de parámetros psicológicos y espirituales de 8.964 pacientes, visitados por 117 profesionales de 29 equipos en un estudio de diseño cuasi-experimental, prospectivo, multcéntrico de un solo grupo pre-test post-test. Resultados: Los resultados muestran mejoras significativas en parámetros como ansiedad (RL 657,64; p<0,001), malestar emociona (RL 757,44; p<0,001), sentido de la vida (RL 248,30; p<0,001) y sentimientos de paz y perdón (RL 190,94; p<0,001). Conclusiones: El efecto positivo de la intervención psicosocial en la reducción de los parámetros psicológicos y espirituales evaluados sugiere que esta es eficaz en el contexto de la atención a personas con enfermedades avanzadas.

Effectiveness of a primary care-based intervention to reduce sitting time in overweight and obese patients (SEDESTACTIV): a randomized controlled trial; rationale and study design

Background: There is growing evidence suggesting that prolonged sitting has negative effects on people's weight, chronic diseases and mortality. Interventions to reduce sedentary time can be an effective strategy to increase daily energy expenditure. The purpose of this study is to evaluate the effectiveness of a six-month primary care intervention to reduce daily of sitting time in overweight and mild obese sedentary patients. Method/Design: The study is a randomized controlled trial (RCT). Professionals from thirteen primary health care centers (PHC) will randomly invite to participate mild obese or overweight patients of both gender, aged between 25 and 65 years old, who spend 6 hours at least daily sitting. A total of 232 subjects will be randomly allocated to an intervention (IG) and control group (CG) (116 individuals each group). In addition, 50 subjects with fibromyalgia will be included. Primary outcome is: (1) sitting time using the activPAL device and the Marshall questionnaire. The following parameters will be also assessed: (2) sitting time in work place (Occupational Sitting and Physical Activity Questionnaire), (3) health-related quality of life (EQ-5D), (4) evolution of stage of change (Prochaska and DiClemente's Stages of Change Model), (5) physical inactivity (catalan version of Brief Physical Activity Assessment Tool), (6) number of steps walked (pedometer and activPAL), (7) control based on analysis (triglycerides, total cholesterol, HDL, LDL, glycemia and, glycated haemoglobin in diabetic patients) and (8) blood pressure and anthropometric variables. All parameters will be assessed pre and post intervention and there will be a follow up three, six and twelve months after the intervention. A descriptive analysis of all variables and a multivariate analysis to assess differences among groups will be undertaken. Multivariate analysis will be carried out to assess time changes of dependent variables. All the analysis will be done under the intention to treat principle. Discussion: If the SEDESTACTIV intervention shows its effectiveness in reducing sitting time, health professionals would have a low-cost intervention tool for sedentary overweight and obese patients management.

Odor emission control and reduce in betaine manufacture

This thesis was made in Naantali plant of Finnfeeds Finland Oy. In this thesis the main study was in reducing, controlling, measuring and processing odour effluents in various methods. Also are considered legislation, marketing issues and environmental requirements of reducing of odour effluents. The literature review introduces odours complications, legislations and various methods of odour removal. There is also a review of volatile organic compounds detection and measuring methods. The experimental section consists TD-GC-MS-measurements and expansive measurements with electronic nose. Electronic nose is a new solution for recognition and measuring industrial odours. In this thesis the electronic nose was adapted into reliable recognition and measuring method. Measurements with electronic nose was made in betaine factory and main targets were odour removal process and other odours from factory. As a result of experimental work with TD-GC-MS-measurements becomes odour compound of 2-and 3- methylbutanal and dimethyldisulfide, which odour is sweet and fug. Extensive study with electronic nose found many developmental subjects. Odour balance measurements of factory and after calculation made adjustment of odour removal process, over all odour effluent to environment will reduce 25 %.

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)-a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group-a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

Variable-stiffness composite panels: Defect tolerance under in-plane tensile loading

Automated Fiber Placement is being extensively used in the production of major composite components for the aircraft industry. This technology enables the production of tow-steered panels, which have been proven to greatly improve the structural efficiency of composites by means of in-plane stiffness variation and load redistribution. However, traditional straight-fiber architectures are still preferred. One of the reasons behind this is related to the uncertainties, as a result of process-induced defects, in the mechanical performance of the laminates. This experimental work investigates the effect of the fiber angle discontinuities between different tow courses in a ply on the un-notched and open-hole tensile strength of the laminate. The influence of several manufacturing parameters are studied in detail. The results reveal that 'ply staggering' and '0% gap coverage' is an effective combination in reducing the influence of defects in these laminates

Designing an undergraduate laboratory course in general chemistry

From an analysis of a learning model based on the theory of information processing four hypothesis were developed for improving the design of laboratory courses. Three of these hypotheses concerned specific procedures to minimise the load on students' working memories (or working spaces) and the fourth hypothesis was concerned with the value of mini-projects in enhancing meaningful learning of the knowledge and skills underpinning the set experiments. A three-year study of a first year undergraduate chemistry laboratory course at a Scottish university has been carried out to test these four hypotheses. This paper reports the results of the study relevant to the three hypotheses about the burden on students' working spaces. It was predicted from the learning model that the load on students working space should be reduced by appropriate changes to the written instructions and the laboratory organisation and by the introduction of prelab-work and prelab-training in laboratory techniques. It was concluded from research conducted over the three years period that all these hypothesised changes were effective both in reducing the load on students' working spaces and in improving their attitudes to the laboratory course.

Real unit labour costs in Eurozone countries: drivers and clusters

We examine the trajectories of the real unit labour costs (RULCs) in a selection of Eurozone economies. Strong asymmetries in the convergence process of the RULCs and its components —real wages, capital intensity, and technology— are uncovered through decomposition and cluster analyses. In the last three decades, the PIIGS (Portugal, Ireland, Italy, Greece, and Spain) succeeded in reducing their RULCs by more than their northern partners. With the exception of Ireland, however, technological progress was weak; it was through capital intensification that periphery economies gained efficiency and competitiveness. Cluster heterogeneity, and lack of robustness in cluster composition, is a reflection of the difficulties in achieving real convergence and, by extension, nominal convergence. We conclude by outlining technology as the key convergence factor, and call for a renewed attention to real convergence indicators to strengthen the process of European integration.