Supporting the improvement of air quality management practices: The "FAIRMODE pilot" activity.

This paper presents the first outcomes of the "FAIRMODE pilot" activity, aiming at improving the way in which air quality models are used in the frame of the European "Air Quality Directive". Member States may use modelling, combined with measurements, to "assess" current levels of air quality and estimate future air quality under different scenarios. In case of current and potential exceedances of the Directive limit values, it is also requested that they "plan" and implement emission reductions measures to avoid future exceedances. In both "assessment" and "planning", air quality models can and should be used; but to do so, the used modelling chain has to be fit-for-purpose and properly checked and verified. FAIRMODE has developed in the recent years a suite of methodologies and tools to check if emission inventories, model performance, source apportionment techniques and planning activities are fit-for-purpose. Within the "FAIRMODE pilot", these tools are used and tested by regional/local authorities, with the two-fold objective of improving management practices at regional/local scale, and providing valuable feedback to the FAIRMODE community. Results and lessons learnt from this activity are presented in this paper, as a showcase that can potentially benefit other authorities in charge of air quality assessment and planning.

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. METHODS: We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. RESULTS: Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. CONCLUSIONS: HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

Resource recovery from sulphate-rich sewage through an innovative anaerobic-based water resource recovery facility (WRRF).

This research work proposes an innovative water resource recovery facility (WRRF) for the recovery of energy, nutrients and reclaimed water from sewage, which represents a promising approach towards enhanced circular economy scenarios. To this aim, anaerobic technology, microalgae cultivation, and membrane technology were combined in a dedicated platform. The proposed platform produces a high-quality solid- and coliform-free effluent that can be directly discharged to receiving water bodies identified as sensitive areas. Specifically, the content of organic matter, nitrogen and phosphorus in the effluent was 45 mg COD·L-1, 14.9 mg N·L-1 and 0.5 mg P·L-1, respectively. Harvested solar energy and carbon dioxide biofixation in the form of microalgae biomass allowed remarkable methane yields (399 STP L CH4·kg-1 CODinf) to be achieved, equivalent to theoretical electricity productions of around 0.52 kWh per m3 of wastewater entering the WRRF. Furthermore, 26.6% of total nitrogen influent load was recovered as ammonium sulphate, while nitrogen and phosphorus were recovered in the biosolids produced (650 ± 77 mg N·L-1 and 121.0 ± 7.2 mg P·L-1).

Wannier-Mott Excitons in Nanoscale Molecular Ices.

The absorption of light to create Wannier-Mott excitons is a fundamental feature dictating the optical and photovoltaic properties of low band gap, high permittivity semiconductors. Such excitons, with an electron-hole separation an order of magnitude greater than lattice dimensions, are largely limited to these semiconductors but here we find evidence of Wannier-Mott exciton formation in solid carbon monoxide (CO) with a band gap of >8 eV and a low electrical permittivity. This is established through the observation that a change of a few degrees K in deposition temperature can shift the electronic absorption spectra of solid CO by several hundred wave numbers, coupled with the recent discovery that deposition of CO leads to the spontaneous formation of electric fields within the film. These so-called spontelectric fields, here approaching 4×10^{7} V m^{-1}, are strongly temperature dependent. We find that a simple electrostatic model reproduces the observed temperature dependent spectral shifts based on the Stark effect on a hole and electron residing several nm apart, identifying the presence of Wannier-Mott excitons. The spontelectric effect in CO simultaneously explains the long-standing enigma of the sensitivity of vacuum ultraviolet spectra to the deposition temperature.

Organization of the Fugu rubripes Hox clusters: evidence for continuing evolution of vertebrate Hox complexes.

The clustered organization of Hox genes provides a powerful opportunity to examine gene gain and loss in evolution because physical linkage is a key diagnostic feature which allows homology to be established unambiguously. Furthermore, Hox genes play a key role in determination of axial and appendicular skeletal morphology and may be a key component of the evolution of diverse metazoan body forms. Despite suggestions that changes in Hox gene number played a role in evolution of metazoan body plans, there has been a general lack of evidence for such variation amongst gnathostomes (or indeed any vertebrate) and it has therefore been widely assumed that differential regulation may be the key element in all vertebrate Hox evolution. We have studied the Hox gene clusters of a teleost fish, Fugu rubripes, to test the possibility that Hox organization may have varied since the origin of jawed vertebrates. We have identified four Hox complexes in Fugu and found an unprecedented degree of variation when compared with tetrapod clusters. Our data show that: Fugu clusters are widely variant with respect to length; at least nine genes have been lost; there is a new group-2 paralogue; and pseudo-gene remnants of group-1 and group-3 paralogues were found in the Hoxc complex, when compared with the present mammalian clusters. We show that gene loss after duplication of the prototypical vertebrate Hox clusters is a key feature of both tetrapod and fish evolution.

Comparison of the correction of the femoral offset after the use of a stem with modular neck and its monoblock homologue in total primary hip arthroplasty. / Comparación de la corrección del offset femoral tras el empleo de un vástago monobloque y un vástago con cuello modular en la artroplastia total de cadera primaria.

INTRODUCTION AND OBJECTIVE: Dual modularity stems were introduced with the theoretical advantage of restoring hip anatomy more precisely through femoral offset and limb length adjustment. Interchangeable necks allow for intraoperative angulation, anteversion and length changes. Our objective is to study whether a better femoral offset correction is achieved with the H MAX-M® prosthesis (Limacorporate, San Daniele, Italy) compared to its monoblock counterpart. MATERIAL AND METHODS: A prospective cohort study was conducted by means of consecutive sampling on adult patients undergoing total hip arthroplasty with the diagnosis of coxarthrosis between January 2011 and December 2015. This cohort has two arms, one arm included patients who underwent modular neck arthroplasty and the other included patients who underwent monoblock total hip arthroplasty. Radiographic offset measurement of the operated hip and the contralateral hip was performed, and the difference between both values was calculated. The mean of the measurements obtained for each arm of the cohort were compared with each other. RESULTS: No statistically significant differences were observed in the difference in offset between the operated hip and the contralateral hip (P=.323). No statistically significant differences were observed in the correction of the femoral offset, determined as the difference between the operated hip and the contralateral hip (P=.323). Nor were differences observed in the postoperative offset values (P=.097). It should be noted that for both designs, the majority group is the one with restored offset (P=.001).

[Value of the direct cystoscintigraphy in the diagnosis of vesicoureteral reflux in patients with prenatal hydronephrosis]. / Valor de la cistogammagrafía directa en el diagnóstico del reflujo vesicoureteral en pacientes con hidronefrosis prenatal.

OBJECTIVE: As the radiation received in conventional cystography is about 20 times higher than radionuclide cystography and the sensitivity of the last is higher in order to diagnose vesicoureteral reflux, we consider the use of radionuclide cystography in early detection of reflux in patients with prenatally detected hydronephrosis. MATERIALS AND METHODS: Between 2003 and 2009, a study of neonates with prenatal history of hydronephrosis was performed in order to rule out reflux. Our protocol was as follows: The diagnosis was confirmed by postnatal ultrasound at 1 week (in this case patient initiate antibiotic prophylaxis). A new ultrasound was repeated at 6 weeks, if the dilatation was larger than 8 mm at this time, direct radionuclide scintigraphy was performed. The patients were placed on prophylactic antibiotics until the screenining results were known. Conventional cystography was performed if a male infant showed severe dilatation, or in general in cases with parenchymatous atrophy or if a duplex system was suspected. RESULTS: In 13 (20%) of the 65 cases (18 kidneys) reflux was detected (3 minor, 8 moderate and 7 severe). In most cases, follow up was performed with radionuclide cystography. None of the patients with reflux placed on prophylactic antibiotics developed a febrile urinary tract infection during the first year of life. CONCLUSIONS: Direct radionuclide cystography is a useful diagnostic method in early detection of vesicoureteral reflux in patients with prenatal hydronephrosis with higher sensitivity than conventional cystography, and with an important advantage concerning radiation of the patient. Patients screened and placed on prophylactic antibiotics are probably going to present less episodes of pielonephrytis.

BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received.

BACKGROUND: Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker. METHODS: Five studies of 11 212 women with early-stage breast cancer were analysed. Individual patient data included tumour size, grade, lymph node status, endocrine therapy, chemotherapy and mortality. BCL2, ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) levels were determined in all tumours. A Cox model incorporating the time-dependent effects of each variable was used to explore the prognostic significance of BCL2. RESULTS: In univariate analysis, ER, PR and BCL2 positivity was associated with improved survival and HER2 positivity with inferior survival. For ER and PR this effect was time dependent, whereas for BCL2 and HER2 the effect persisted over time. In multivariate analysis, BCL2 positivity retained independent prognostic significance (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.66-0.88, P<0.001). BCL2 was a powerful prognostic marker in ER- (HR 0.63, 95% CI 0.54-0.74, P<0.001) and ER+ disease (HR 0.56, 95% CI 0.48-0.65, P<0.001), and in HER2- (HR 0.55, 95% CI 0.49-0.61, P<0.001) and HER2+ disease (HR 0.70, 95% CI 0.57-0.85, P<0.001), irrespective of the type of adjuvant therapy received. Addition of BCL2 to the Adjuvant! Online prognostic model, for a subset of cases with a 10-year follow-up, improved the survival prediction (P=0.0039). CONCLUSIONS: BCL2 is an independent indicator of favourable prognosis for all types of early-stage breast cancer. This study establishes the rationale for introduction of BCL2 immunohistochemistry to improve prognostic stratification. Further work is now needed to ascertain the exact way to apply BCL2 testing for risk stratification and to standardise BCL2 immunohistochemistry for this application.

Familial C4B deficiency and immune complex glomerulonephritis.

Homozygous complement C4B deficiency is described in a Southern European young female patient with Membranoproliferative Glomerulonephritis (MPGN) type III characterized by renal biopsies with strong complement C4 and IgG deposits. Low C4 levels were independent of clinical evolution or type of immunosuppression and were found in three other family members without renal disease or infections. HLA typing revealed that the patient has homozygous A*02, Cw*06, B*50 at the class I region, and DRB1*08 and DQB1*03 at the class II region. Genotypic and phenotypic studies demonstrated that the patient has homozygous monomodular RCCX in the HLA class III region, with single long C4A genes coding for C4A3 and complete C4B deficiency. Her father, mother, son and niece have heterozygous C4B deficiency. The patient's deceased brother had a history of Henoch-Schönlein Purpura (HSP), an immune complex-mediated proliferative glomerulonephritis. These findings challenge the putative pathophysiological roles of C4A and C4B and underscore the need to perform functional assays, C4 allotyping and genotyping on patients with persistently low serum levels of a classical pathway complement component and glomerulopathy associated with immune deposits.

Nitrite inhibition of microalgae induced by the competition between microalgae and nitrifying bacteria.

Outdoor microalgae cultivation systems treating anaerobic membrane bioreactor (AnMBR) effluents usually present ammonium oxidising bacteria (AOB) competition with microalgae for ammonium uptake, which can cause nitrite accumulation. In literature, nitrite effects over microalgae have shown controversial results. The present study evaluates the nitrite inhibition role in a microalgae-nitrifying bacteria culture. For this purpose, pilot- and lab-scale assays were carried out. During the continuous outdoor operation of the membrane photobioreactor (MPBR) plant, biomass retention time (BRT) of 2 d favoured AOB activity, which caused nitrite accumulation. This nitrite was confirmed to inhibit microalgae performance. Specifically, continuous 5-d lab-scale assays showed a reduction in the nitrogen recovery efficiency by 32, 42 and 80% when nitrite concentration in the culture accounted for 5, 10 and 20 mg N·L-1, respectively. On the contrary, short 30-min exposure to nitrite showed no significant differences in the photosynthetic activity of microalgae under nitrite concentrations of 0, 5, 10 and 20 mg N·L-1. On the other hand, when the MPBR plant was operated at 2.5-d BRT, the nitrite concentration was reduced to negligible values due to increasing activity of microalgae and nitrite oxidising bacteria (NOB). This allowed obtaining maximum MPBR performance; i.e. nitrogen recovery rate (NRR) and biomass productivity of 19.7 ± 3.3 mg N·L-1·d-1 and 139 ± 35 mg VSS·L-1·d-1, respectively; while nitrification rate (NOxR) reached the lowest value (13.5 ± 3.4 mg N·L-1·d-1). Long BRT of 4.5 d favoured NOB growth, avoiding nitrite inhibition. However, it implied a decrease in microalgae growth and the accumulation of nitrate in the MPBR effluent. Hence, it seems that optimum BRT has to be within the range 2-4.5 d in order to favour microalgae growth with respect to AOB and NOB.

Improving membrane photobioreactor performance by reducing light path: operating conditions and key performance indicators.

Microalgae cultivation has been receiving increasing interest in wastewater remediation due to their ability to assimilate nutrients present in wastewater streams. In this respect, cultivating microalgae in membrane photobioreactors (MPBRs) allows decoupling the solid retention time (SRT) from the hydraulic retention time (HRT), which enables to increase the nutrient load to the photobioreactors (PBRs) while avoiding the wash out of the microalgae biomass. The reduction of the PBR light path from 25 to 10 cm increased the nitrogen and phosphorus recovery rates, microalgae biomass productivity and photosynthetic efficiency by 150, 103, 194 and 67%, respectively.The areal biomass productivity (aBP) also increased when the light path was reduced, reflecting the better use of light in the 10-cm MPBR plant. The capital and operating operational expenditures (CAPEX and OPEX) of the 10-cm MPBR plant were also reduced by 27 and 49%, respectively. Discharge limits were met when the 10-cm MPBR plant was operated at SRTs of 3-4.5 d and HRTs of 1.25-1.5 d. At these SRT/HRT ranges, the process could be operated without a high fouling propensity with gross permeate flux (J20) of 15 LMH and specific gas demand (SGDp) between 16 and 20 Nm3air·m-3permeate, which highlights the potential of membrane filtration in MPBRs. When the continuous operation of the MPBR plant was evaluated, an optical density of 680 nm (OD680) and soluble chemical oxygen demand (sCOD) were found to be good indicators of microalgae cell and algal organic matter (AOM) concentrations, while dissolved oxygen appeared to be directly related to MPBR performance. Nitrite and nitrate (NOx) concentration and the soluble chemical oxygen demand:volatile suspended solids ratio (sCOD:VSS) were used as indicators of nitrifying bacteria activity and the stress on the culture, respectively. These parameters were inversely related to nitrogen recovery rates and biomass productivity and could thus help to prevent possible culture deterioration.

[The role of eslicarbazepine acetate in the treatment of focal-onset epilepsy in pediatric age: practical issues]. / Papel del acetato de eslicarbazepina en el tratamiento de la epilepsia de origen focal en la edad pediátrica: consideraciones prácticas.

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug (AED) of the carboxamide family and structurally related to carbamazepine and oxcarbazepine, although it has pharmacological differences that may have relevant implications of clinical utility. Since 2009 in Europe, ESL has been indicated for use in adults as adjuvant therapy in patients with partial-onset seizures (currently called focal-onset), with or without secondary generalization (with or without evolution to bilateral tonic-clonic, in current terminology). In 2017, the indication for adjunctive therapy of patients with partial-onset seizures with or without secondary generalization was extended to its use as monotherapy in adults and as adjuvant therapy in adolescents and children older than 6 years. A group of experts carried out this review aimed at the aspects of most interest in the clinical practice of the use of ESL in the pediatric population, including differential aspects from other AEDs. Aspects such as efficacy, dosage, clinical response depending on age, tolerability and its management, neurocognitive and behavioral profile, need for monitoring of any analytical parameter, role of plasma level monitoring, possible added value of the once-daily administration, clinical situations in which the addition of ESL would be recommended, use with other sodium channel blockers, how to switch from carbamazepine/oxcarbazepine, potential interactions with other AEDs, potential interactions with drugs other than AEDs, and some practical issues that require additional research.

TITLE: Papel del acetato de eslicarbazepina en el tratamiento de la epilepsia de origen focal en la edad pediátrica: consideraciones prácticas.El acetato de eslicarbazepina (ESL) es un fármaco antiepiléptico (FAE) de tercera generación de la familia de las carboxamidas y estructuralmente relacionado con la carbamazepina y la oxcarbazepina, aunque presenta diferencias farmacológicas que pueden tener implicaciones de utilidad clínica relevantes. Desde 2009, en Europa, el ESL está indicado para su utilización en adultos como terapia adyuvante en pacientes con crisis de inicio parcial (actualmente denominada de inicio focal), con o sin generalización secundaria (con o sin evolución a tonicoclónica bilateral, en terminología actual). En 2017, la indicación como tratamiento adyuvante de los pacientes con crisis de inicio parcial con o sin generalización secundaria se amplió a su utilización en monoterapia en adultos y en combinación en adolescentes y niños mayores de 6 años. Un grupo de expertos realizó esta revisión orientada a la práctica clínica del uso de ESL en población pediátrica, incluyendo aquellos puntos diferenciales respecto a otros FAE. Se han incluido aspectos como la eficacia, dosificación, respuesta clínica en función de la edad, tolerabilidad y su manejo, perfil neurocognitivo y conductual, necesidad de control de algún parámetro analítico, papel de la monitorización de los niveles plasmáticos, posible valor añadido de la administración única, situaciones clínicas en las que sería recomendable la adición de ESL, utilización con otros bloqueantes de los canales del sodio, realización del cambio desde carbamazepina/oxcarbazepina, potenciales interacciones con otros FAE, potenciales interacciones con otros fármacos distintos de los FAE, y algunas consideraciones prácticas que requieren una investigación adicional.

Atmospheric transport is a major pathway of microplastics to remote regions.

In recent years, marine, freshwater and terrestrial pollution with microplastics has been discussed extensively, whereas atmospheric microplastic transport has been largely overlooked. Here, we present global simulations of atmospheric transport of microplastic particles produced by road traffic (TWPs - tire wear particles and BWPs - brake wear particles), a major source that can be quantified relatively well. We find a high transport efficiencies of these particles to remote regions. About 34% of the emitted coarse TWPs and 30% of the emitted coarse BWPs (100 kt yr-1 and 40 kt yr-1 respectively) were deposited in the World Ocean. These amounts are of similar magnitude as the total estimated direct and riverine transport of TWPs and fibres to the ocean (64 kt yr-1). We suggest that the Arctic may be a particularly sensitive receptor region, where the light-absorbing properties of TWPs and BWPs may also cause accelerated warming and melting of the cryosphere.

Regulation of maternal behavior and offspring growth by paternally expressed Peg3.

Imprinted genes display parent-of-origin-dependent monoallelic expression that apparently regulates complex mammalian traits, including growth and behavior. The Peg3 gene is expressed in embryos and the adult brain from the paternal allele only. A mutation in the Peg3 gene resulted in growth retardation, as well as a striking impairment of maternal behavior that frequently resulted in death of the offspring. This result may be partly due to defective neuronal connectivity, as well as reduced oxytocin neurons in the hypothalamus, because mutant mothers were deficient in milk ejection. This study provides further insights on the evolution of epigenetic regulation of imprinted gene dosage in modulating mammalian growth and behavior.

Effect of ambient temperature variations on an indigenous microalgae-nitrifying bacteria culture dominated by Chlorella.

Two outdoor photobioreactors were operated to evaluate the effect of variable ambient temperature on an indigenous microalgae-nitrifying bacteria culture dominated by Chlorella. Four experiments were carried out in different seasons, maintaining the temperature-controlled PBR at around 25 °C (by either heating or cooling), while the temperature in the non-temperature-controlled PBR was allowed to vary with the ambient conditions. Temperatures in the range of 15-30 °C had no significant effect on the microalgae cultivation performance. However, when the temperature rose to 30-35 °C microalgae viability was significantly reduced. Sudden temperature rises triggered AOB growth in the indigenous microalgae culture, which worsened microalgae performance, especially when AOB activity made the system ammonium-limited. Microalgae activity could be recovered after a short temperature peak over 30 °C once the temperature dropped, but stopped when the temperature was maintained around 28-30 °C for several days.

Primary total hip arthroplasty with fourth-generation ceramic bearings: Clinical and survival results with a minimum follow-up of 5 years. / Prótesis total de cadera primaria con par de fricción cerámica sobre cerámica de cuarta generación: resultados clínicos y de supervivencia con un seguimiento mínimo de 5 años.

OBJECTIVE: To evaluate the clinical results and survival of primary hip prosthesis with ceramic delta bearings (C-C) with a minimum follow-up of 5years. MATERIAL AND METHOD: A total of 205 primary hip arthroplasties performed between 2008 and 2012 were studied. The clinical results, pre-surgical and at 5years of follow-up were evaluated using the Harris Hip Score (HHS), the Short Form-36 (SF-36), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the visual analogue scale (VAS). The position of the prosthetic components, periprosthetic osteolysis, loosening of the prosthetic components and ruptures of the ceramic components were studied radiologically. The adverse events related to bearings were recorded according to their diameter, paying special attention to prosthetic dislocations and the presence of noise. Survival with an endpoint of prosthetic revision for any cause was estimated using the Kaplan-Meier method. RESULTS: Significant improvements were obtained in the HHS (88.7% of good/excellent results), SF36, WOMAC and EVA, P<.001. There were 19 adverse events related to the prosthesis (4 periprosthetic fractures, 4 dislocations, 2 superficial infections, 1 mobilization of the cup, 2 noises, 4 aseptic loosenings and 2 breaks of the prosthetic neck); 47.3% needed revision. The cumulative survival of the prostheses was 97.5% (95%CI: 96.4-98.5). No differences were found in survival, prosthetic adverse events, noise incidence or dislocations and clinical results among the different diameters used. CONCLUSIONS: Primary hip prostheses with fourth-generation ceramic bearings showed good survival in the medium term, and good clinical results.

p300 is required for orderly G1/S transition in human cancer cells.

The role of the transcriptional coactivator p300 in cell cycle control has not been analysed in detail due to the lack of appropriate experimental systems. We have now examined cell cycle progression of p300-deficient cancer cell lines, where p300 was disrupted either by gene targeting (p300(-) cells) or knocked down using RNAi. Despite significant proliferation defects under normal growth conditions, p300-deficient cells progressed rapidly through G1 with premature S-phase entry. Accelerated G1/S transition was associated with early retinoblastoma (RB) hyperphosphorylation and activation of E2F targets. The p300-acetylase activity was dispensable since expression of a HAT-deficient p300 mutant reversed these changes. Co-immunoprecipitation showed p300/RB interaction occurs in vivo during G1, and this interaction has two peaks: in early G1 with unphosphorylated RB and in late G1 with phosphorylated RB. In vitro kinase assays showed that p300 directly inhibits cdk6-mediated RB phosphorylation, suggesting p300 acts in early G1 to prevent RB hyperphosphorylation and delay premature S-phase entry. Paradoxically, continued cycling of p300(-) cells despite prolonged serum depletion was observed, and this occurred in association with persistent RB hyperphosphorylation. Altogether, these results suggest that p300 has an important role in G1/S control, possibly by modulating RB phosphorylation.

A gene-expression signature to predict survival in breast cancer across independent data sets.

Prognostic signatures in breast cancer derived from microarray expression profiling have been reported by two independent groups. These signatures, however, have not been validated in external studies, making clinical application problematic. We performed microarray expression profiling of 135 early-stage tumors, from a cohort representative of the demographics of breast cancer. Using a recently proposed semisupervised method, we identified a prognostic signature of 70 genes that significantly correlated with survival (hazard ratio (HR): 5.97, 95% confidence interval: 3.0-11.9, P = 2.7e-07). In multivariate analysis, the signature performed independently of other standard prognostic classifiers such as the Nottingham Prognostic Index and the 'Adjuvant!' software. Using two different prognostic classification schemes and measures, nearest centroid (HR) and risk ordering (D-index), the 70-gene classifier was also found to be prognostic in two independent external data sets. Overall, the 70-gene set was prognostic in our study and the two external studies which collectively include 715 patients. In contrast, we found that the two previously described prognostic gene sets performed less optimally in external validation. Finally, a common prognostic module of 29 genes that associated with survival in both our cohort and the two external data sets was identified. In spite of these results, further studies that profile larger cohorts using a single microarray platform, will be needed before prospective clinical use of molecular classifiers can be contemplated.

Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers.

We analysed 148 primary breast cancers using BAC-arrays containing 287 clones representing cancer-related gene/loci to obtain genomic molecular portraits. Gains were detected in 136 tumors (91.9%) and losses in 123 tumors (83.1%). Eight tumors (5.4%) did not have any genomic aberrations in the 281 clones analysed. Common (more than 15% of the samples) gains were observed at 8q11-qtel, 1q21-qtel, 17q11-q12 and 11q13, whereas common losses were observed at 16q12-qtel, 11ptel-p15.5, 1p36-ptel, 17p11.2-p12 and 8ptel-p22. Patients with tumors registering either less than 5% (median value) or less than 11% (third quartile) total copy number changes had a better overall survival (log-rank test: P=0.0417 and P=0.0375, respectively). Unsupervised hierarchical clustering based on copy number changes identified four clusters. Women with tumors from the cluster with amplification of three regions containing known breast oncogenes (11q13, 17q12 and 20q13) had a worse prognosis. The good prognosis group (Nottingham Prognostic Index (NPI)

Structure-composition relationships in ternary solvents containing methylbenzoate.

Thermophysical properties of the hexane+1-chlorohexane (or hexanoic acid or diisopropylether)+methylbenzoate ternary systems and their binary constituents are reported at 298.15 K and 0.1 MPa over the whole composition range. The properties and the optimized geometry of the gas-phase components were appraised from the density functional theory. To find out the causal link between the thermophysical measurements and the molecular level features, the derived mixing and excess functions of the ternary systems were looked into according to the scaled particle and Kirkwood-Buff analyses. The hydrogen bonding and dipole interactions along with the geometry effects brought about by the very different size and shape of the components give rise to complex mixed structures. Application of semiempirical models and use of simple cubic equations of state combined with a one-parameter van der Waals mixing rule has led to prediction of the ternary properties with variable degree of precision.