Granulocyte colony-stimulating factor receptor signalling via Janus kinase 2/signal transducer and activator of transcription 3 in ovarian cancer

Ovarian cancer remains a major cause of cancer mortality in women, with only limited understanding of disease aetiology at the molecular level. Granulocyte colony-stimulating factor (G-CSF) is a key regulator of both normal and emergency haematopoiesis, and is used clinically to aid haematopoietic recovery following ablative therapies for a variety of solid tumours including ovarian cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors in advanced squamous cell carcinoma of the lung: a meta-analysis.

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are well established in treating metastatic pulmonary adenocarcinoma, especially patients with activating EGFR mutations. EGFR mutations are rare in pulmonary squamous cell carcinomas (SCCs). There are conflicting data supporting the efficacy of EGFR-TKIs in advanced lung SCC. We analyzed the impact of EGFR-TKIs on progression-free survival (PFS) and overall survival (OS) in unselected patients with lung SCC.

Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.

A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 μM and 29-151 μM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken.

Identification of a gene for an ancient cytokine, interleukin 15-like, in mammals; interleukins 2 and 15 co-evolved with this third family member, all sharing binding motifs for IL-15Rα

Interleukins 2 and 15 (IL-2 and IL-15) are highly differentiated but related cytokines with overlapping, yet also distinct functions, and established benefits for medical drug use. The present study identified a gene for an ancient third IL-2/15 family member in reptiles and mammals, interleukin 15-like (IL-15L), which hitherto was only reported in fish. IL-15L genes with intact open reading frames (ORFs) and evidence of transcription, and a recent past of purifying selection, were found for cattle, horse, sheep, pig and rabbit. In human and mouse the IL-15L ORF is incapacitated. Although deduced IL-15L proteins share only ~21 % overall amino acid identity with IL-15, they share many of the IL-15 residues important for binding to receptor chain IL-15Rα, and recombinant bovine IL-15L was shown to interact with IL-15Rα indeed. Comparison of sequence motifs indicates that capacity for binding IL-15Rα is an ancestral characteristic of the IL-2/15/15L family, in accordance with a recent study which showed that in fish both IL-2 and IL-15 can bind IL-15Rα. Evidence reveals that the species lineage leading to mammals started out with three similar cytokines IL-2, IL-15 and IL-15L, and that later in evolution (1) IL-2 and IL-2Rα receptor chain acquired a new and specific binding mode and (2) IL-15L was lost in several but not all groups of mammals. The present study forms an important step forward in understanding this potent family of cytokines, and may help to improve future strategies for their application in veterinarian and human medicine.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Adding a new anticoagulant or antiplatelet agent for patient receiving aspirin after an acute coronary syndrome? - Results from a pairwise and network meta-analysis of randomized-controlled trials

 Objectives: To synthesize the efficacy and safety outcomes from randomized-controlled trials (RCTs) regarding new oral anticoagulant, protease-activated receptor-1 (PAR-1) antagonist, and warfarin adjunctive to aspirin for patients after acute coronary syndrome (ACS) via pair-wise and network meta-analyses.
Methods: A comprehensive literature search was performed in Embase, Medline, Cochrane Library Web of Knowledge, and Scopus. The pair-wise meta-analysis was undertaken respectively to each agent/treatment category via Revmen 5.1. In order to estimate the relative efficacy of each agent/treatment category whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using both fixed- and random-effects model. Covariate analysis was performed to explore the effects of length of follow-up and age of subject on the final results.
Results: In total, 23 RCTs were included in the meta-analysis. As shown by the results (OR,95%CI) for the pair-wise meta-analysis, new oral anticoagulants (0.85, [0.78, 0.93] and 3.04, [2.21, 4.19]), PAR-1 antagonists (0.80, [0.52, 1.22] and 1.55, [1.25, 1.93]) and warfarin (0.87, [0.74, 1.02] and 1.77, [1.46, 2.14]) might be able to provide better outcome in the incidences of major adverse events (MAE) but with higher bleeding risk comparing to aspirin treatment alone. Based on the model fit assessment, the random-effects model was adopted. The network meta-analysis (treatment effect comparing to aspirin lone) identified ximelagatran (-0.3044, [-0.8601, 0.2502]), dabigatran (-0.2144, [-0.8666, 0.4525]), rivoroxaban (-0.2179, [-0.5986, 0.1628]) and vorapaxar (-0.2272, [-0.81, 0.1664]) produced better improvements in MAE incidences whereas vorapaxar (0.3764, [-0.4444, 1.124]), warfarin (0.663, [0.3375, 1.037]), ximelagatran (0.7509, [-0.4164, 2.002]) and apixaban (0.8594, [-0.0049, 1.7]) produced less major bleeding events. The indirect comparisons among drug category (difference in incidence comparing to aspirin lone) showed new oral anticoagulants (-0.1974, [-0.284, -0.111]) and PAR-1 antagonists (-0.1239, [-0.215, -0.033]) to besuperior to warfarin (-0.1004, [-0.166, -0.035]) in the occurrences of MAE whereas PAR-1 antagonists (0.4292, [0.2123, 0.6476]) afforded better outcomes in major bleeding events against warfarin (0.5742, [0.3889, 0.7619]) and new oral anticoagulants (1.169, [0.8667, 1.485]).
Conclusion: Based on the study results, we cannot recommend the routine administration of new oral anticoagulant as add-on treatment for patients after ACS. However, for ACS patients comorbid with atrial fibrillation, new oral anticoagulant might be superior to warfarin in both efficacy and safety outcomes.

Systematic approach to the quantitative voltammetric analysis of the Fe III /Fe II component of the [α 2 -Fe(OH 2 )P 2 W 17 O 61 ] 7-/8- reduction process in buffered and unbuffered aqueous media

The one-electron reduction of [α2-FeIII(OH2)P2W17O61]7- at a glassy carbon electrode was investigated using cyclic and rotating-disk-electrode voltammetry in buffered and unbuffered aqueous solutions over the pH range 3.45−7.50 with an ionic strength of approximately 0.6 M maintained. The behavior is well-described by a square-scheme mechanism P + e- ↔ Q (E10/ = −0.275 V, k10/ = 0.008 cm s-1, and α1 = 1/2), PH+ + e- ↔ QH+ (E20/ = −0.036 V, k20/ = 0.014 cm s-1, and α2 = 1/2), PH+ ↔ P + H+ (KP = 3.02 × 10-6 M), and QH+ ↔ Q + H+ (KQ = 2.35 × 10-10 M), where P, Q, PH+, and QH+ correspond to [α2-FeIII(OH)P2W17O61]8-, [α2-FeII(OH)P2W17O61]9-, [α2-FeIII(OH2)P2W17O61]7-, and [α2-FeII(OH2)P2W17O61]8-, respectively; E10‘ and E20‘ are the formal potentials, k10‘ and k20‘ are the formal (standard) rate constants, and KP and KQ are the acid dissociation constants for the relevant reactions. The analysis for the buffered media is based on the approach of Laviron who demonstrated that a square scheme with fully reversible protonations, reversible or quasi reversible electron transfers with the assumption that α1 = α2, can be well-described by the behavior of a simple redox couple, ox + e- ↔ red, whose formal potential, Eapp0‘, and standard rate constant, kapp0‘, are straightforwardly derived functions of pH, as are the values of E10‘, k10‘, E20‘, k20‘, and KP (only three of the four thermodynamic parameters in a square scheme can be specified). It was assumed that αapp = 1/2, and the simulation program DigiSim was used to determine the values of Eapp0‘ and kapp0‘, which are required to describe the cyclic voltammograms obtained in buffered media in the pH range from 3.45 to 7.52 (buffer-related reactions which effect general acid−base catalysis are included in the simulations). DigiSim simulations of cyclic voltammograms obtained in unbuffered media yielded the values of E10‘ and k10‘; KQ was then directly computed from thermodynamic constraints. These simulations included additional reactions between the redox species and H2O. The value of the diffusion coefficient of the [α2-FeIII(OH2)P2W17O61]7-, 2.92 × 10-6 cm2 s-1, was determined using DigiSim simulations of voltammograms at a rotating disk electrode in buffered and unbuffered media at pH 3.45. The diffusion coefficients of all redox species were assumed to be identical. When the pH is greater than 6, instability of P (i.e., [α2-FeIII(OH)P2W17O61]8-) led to the loss of the reactant and precluded lengthy experimentation.

Functional genomic analysis of systemic cell division regulation in legumes

Legumes develop root nodules from pluripotent stem cells in the rootpericycle in response to mitogenic activation by a decorated chitin-likenodulation factor synthesized in Rhizobium bacteria. The soybean genes encoding the receptor for such signals were cloned using map-based cloning approaches. Pluripotent cells in the root pericycle and the outer or inner cortex undergo repeated cell divisions to initiate a composite nodule primordium that develops to a functional nitrogen-fixing nodule. The process itself is autoregulated, leading to the characteristic nodulation of the upper root system. Autoregulation of nodulation (AON) in all legumes is controlled in part by a leucine-rich repeat receptor kinase gene (GmNARK). Mutations of GmNARK, and its other legume orthologues, result in abundant nodulation caused by the loss of a yet-undefined negative nodulation repressor system. AON receptor kinases are involved in perception of a long distance, root-derived signal, to negatively control nodule proliferation. GmNARK and LjHAR1 are expressed in phloem parenchyma. GmNARK kinase domain interacts with Kinase Associated Protein Phosphatase (KAPP). NARK gene expression did not mirror biological NARK activity in nodulation control, as q-RT-PCR in soybean revealed high NARK expression in roots, root tips, leaves, petioles, stems and hypocotyls, while shoot and root apical meristems were devoid of NARK RNA. High through-put transcript analysis in soybean leaf and root indicated that major genes involved in JA synthesis or response are preferentially down-regulated in leaf but not root of wild type, but not NARK mutants, suggesting that AON signaling may in part be controlled by events relating to hormone metabolism. Ethylene and abscisic acid insensitive mutants of L. japonicus are described. Nodulation in legumes has significance to global economies and ecologies, as the nitrogen input into the biosphere allows food, feed and biofuel production without the inherent costs associated with nitrogen fertilization [1]. Nodulation involves the production of a new organ capable of nitrogen fixation [2] and as such is an excellent system to study plant – microbe interaction, plant development, long distance signaling and functional genomics of stem cell proliferation [3, 4]. Concerted international effort over the last 20 years, using a combination of induced mutagenesis followed by gene discovery (forward genetics), and molecular/biochemical approaches revealed a complex developmental pathway that ‘loans’ genetic programs from various sources and orchestrates these into a novel contribution. We report our laboratory’s contribution to the present analysis in the field.

Ações da dihidrotestosterona sobre a proliferação celular, expressão do receptor de androgênios, bcl-2 e p21 em células prostáticas humanas não transformadas

Hiperplasia Prostática Benigna (HPB) é uma condição patológica que acomete os homens na senescência e está presente em 50% da população masculina, com cerca de 85 anos de idade. A glândula prostática é alvo dos hormônios androgênicos que são responsáveis pela diferenciação e crescimento do epitélio e estroma prostáticos. Os mecanismos proliferativos da próstata envolvem uma série de fatores que operam em conjunto para manter o equilíbrio entre inibição e/ou proliferação celular. Este trabalho teve como objetivo investigar os mecanismos moleculares mediados por androgênio que possam estar envolvidos na proliferação de células epiteliais prostáticas humanas derivadas de HPB. As células foram incubadas com diferentes concentrações de dihidrotestosterona (DHT). Uma baixa concentração de DHT (10-13 M) provocou um aumento significativo na proliferação destas células. Para se verificar se o efeito proliferativo ocorre via receptor de androgênio (AR), as células foram tratadas com o antiandrogênio hidroxiflutamida e a proliferação foi inibida. A expressão do gene do AR foi avaliada por RT-PCR em diferentes tempos de tratamento e concentrações de DHT. Os níveis de mRNA do AR aumentaram significativamente nos grupos tratados com DHT.10-13 M em 3, 4 e 6 horas de estímulo hormonal, sendo que um aumento marcante na expressão do AR foi observado em 4 horas de tratamento. Em relação às diferentes concentrações de DHT testadas no tempo de 4 horas (DHT.10-8, DHT.10-10 e DHT.10-13 M), a expressão do AR aumentou significativamente no grupo tratado com DHT.10-13 M em relação ao grupo controle. Buscando averiguar o possível papel de genes envolvidos na proliferação celular que podem ser modulados pela ação androgênica, em células epiteliais prostáticas, avaliou-se também por RT-PCR a expressão do p21 e do bcl-2. A expressão gênica do p21 foi verificada no intervalo de tempo de zero à 6 horas de tratamento com DHT.10-13 M, não apresentando diferença em seus níveis de mRNA nos tempos avaliados. Quando as células foram incubadas durante 4 horas com diferentes concentrações de DHT, observou-se que a concentração mais alta (10-8 M) provocou um aumento significativo nos níveis de mRNA do p21 em relação ao grupo tratado com DHT.10-13 M. O gene do bcl-2 teve sua expressão avaliada no mesmo intervalo de tempo do p21. Os níveis de mRNA do bcl-2 aumentaram significativamente em 15 minutos de tratamento com DHT.10-13 M em relação ao tempo zero e aos grupos tratados por 1 e 4 horas. Os dados obtidos neste trabalho indicam que baixas concentrações de dihidrotestosterona estimulam a proliferação das células epiteliais prostáticas derivadas de HPB, por uma via que parece envolver a expressão do AR, do p21 e do bcl-2.

Expressão gênica do receptor estrogênico-a, bcl-2 e c-myc em fibroadenomas e no tecido mamário normal circunjacente

Resumo não disponível.

Voice over IP 2.0: an analysis of limits and potential of IP2IP telecommunication

Internet Telephony (VoIP) is changing the telecommunication industry. Oftentimes free, VoIP is becoming more and more popular amongst users. Large software companies have entered the market and heavily invest into it. In 2011, for instance, Microsoft bought Skype for 8.5bn USD. This trend increasingly impacts the incumbent telecommunication operators. They see their main source of revenue – classic telephony – under siege and disappear. The thesis at hand develops a most-likely scenario in order to determine how VoIP is evolving further and it predicts, based on a ten-year forecast, the impact it will have on the players in the telecommunication industry.The paper presents a model combining Rogers’ diffusion and Christensen’s innovation research. The model has the goal of explaining the past evolution of VoIP and to isolate the factors that determine the further diffusion of the innovation. Interviews with industry experts serve to assess how the identified factors are evolving.Two propositions are offered. First, VoIP operators are becoming more important in international, corporate, and mobile telephony. End-to-end VoIP (IP2IP) will exhibit strong growth rates and increasingly cannibalize the telephony revenues of the classic operators. Second, fix-net telephony in SMEs and at home will continue to be dominated by the incumbents. Yet, as prices for telephony fall towards zero also they will implement IP2IP in order to save costs. By 2022, up to 90% of the calls will be IP2IP. The author recommends the incumbents and VoIP operators to proactively face the change, to rethink their business strategies, and to even be open for cooperation.

Associação do receptor toll-like 2 com o estado pró-inflamatório do diabetes tipo 1

Inflammation has been pointed out as an important factor in development of chronic diseases, as diabetes. Hyperglycemia condition would be responsible by toll-like receptors, TLR2 and TLR4, and, consequently by local and systemic inflammation induction. Thus, the objective of present study was to evaluate type 1 Diabetes mellitus (T1DM) pro-inflammatory state through mRNA expression of TLRs 2 and 4 and proinflammatory cytokines IL-1β, IL-6 and TNF-α correlating to diabetic nephropathy. In order to achieve this objective, 76 T1DM patients and 100 normoglycemic (NG) subjects aged between 6 and 20 years were evaluated. T1DM subjects were evaluated as a total group DM1, and considering glycemic control (good glycemic control DM1G, and poor glycemic control DM1P) and considering time of diagnosis (before achieving 5 years of diagnosis DM1< 5yrs, and after achieving 5 years of diagnosis DM1 <5yrs). Metabolic control was evaluated by glucose and glycated hemoglobin concentrations; to assess renal function serum urea, creatinine, albumin, total protein and urinary albumin-to-creatinine ratio were determined and to evaluate hepatic function, AST and ALT serum activities were measured. Pro-inflammatory status was assessed by mRNA expression of TLRs 2 and 4 and the inflammatory cytokines IL-1β, IL-6 and TNF-α. Except for DM1G group (18.4%), DM1NC patients (81.6%) showed a poor glycemic control, with glycated hemoglobin (11,2%) and serum glucose (225,5 md/dL) concentrations significantly increased in relation to NG group (glucose: 76,5mg/dL and glycated hemoglobin: 6,9%). Significantly enhanced values of urea (20%) and ACR (20,8%) and diminished concentrations of albumin (5,7%) and total protein (13,6%) were found in T1DM patients, mainly associated to a poor glycemic control (DM1P increased values of urea: 20% and ACR:49%, and diminished of albumin: 13,6% and total protein:13,6%) and longer disease duration (DM1 <5yrs - increased values of urea: 20% and ACR:20,8%, and diminished of albumin: 14,3% and total protein:13,6%). As regarding pro-inflammatory status evaluation, significantly increased mRNA expressions were presented for TLR2 (37,5%), IL-1β (43%), IL-6 (44,4%) and TNF-α (15,6%) in T1DM patients in comparison to NG, mainly associated to DM1P (poor glycemic control TLR2: 82%, IL-1β: 36,8% increase) and DM1 <5yrs (longer time of diagnosis TLR2: 85,4%, IL-1β: 46,5% increased) groups. Results support the existence of an inflammatory state mediated by an increased expression of TLR2 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in T1DM

Synthesis, characterization and biological analysis of the complex [VO(Hdhp)(2)] (H(2)dhp=2,3-dihydroxypyridine)

A new vanadium (IV) complex with the monoanion of 2,3-dihydroxypyridine (H(2)dhp), or 3-hydroxy-2(1H)-pyridone, was synthesized, characterized by physicochemical techniques and tested biologically. The EPR data for the [VO(Hdhp)(2)] complex in DMF are: g(x) = 1.9768, g(y) = 1.9768 and g(z) = 1.9390; A values (10(-4) cm(-1)): A(x), 59.4; A(y//), 59.4; A(z), 171.0. The vV=O band in the IR spectrum of the complex is at 986 cm(-1). The complex is paramagnetic, with mu(eff) = 1.65 BM (d(1), spin-only) at 25 degrees C. The irreversible oxidation process [V(V)/V(IV)] of the [VO(Hdhp)(2)] complex, as revealed in a cyclic voltammogram, occurs at 876 mV. The calculated molecular structure of [VO(Hdhp)(2)] shows the vanadium(IV) center in a distorted square pyramidal environment, with the oxo ligand in the apical position and the oxygen donor atoms of the Hdhp ligands in the basal positions. The ability of [VO(Hdhp)(2)] to mimic insulin, and its toxicity to hepato-biliary functions, were investigated in streptozotocin-induced diabetic rats and it was concluded that the length of treatment and the amount of [VO(Hdhp)(2)] administered were effective in reducing experimental diabetes.