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Introduction: Endemic coronaviruses have been found in acute bronchiolitis, mainly as a coinfecting virus. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for respiratory illness in hospitalized children. The characteristics of patients with bronchiolitis have not been extensively described. Methods: Cross-sectional study of patients with bronchiolitis and SARS-CoV-2 infection enrolled in a prospective multicenter cohort of children hospitalized with COVID-19 in Spain from March 1, 2020 to February 28, 2021. Results: Twelve of 666 children infected with SARS-CoV-2 who required hospital admission met the diagnostic criteria for bronchiolitis (1.8%). Median age was 1.9 months (range: 0.4-10.1). Six cases had household contact with a confirmed or probable COVID-19 case. Main complaints were cough (11 patients), rhinorrhea (10), difficulty breathing (8), and fever (8). Eleven cases were classified as mild or moderate and one as severe. Laboratory tests performed in seven patients did not evidence anemia, lymphopenia, or high C-reactive protein levels. Chest X-rays were performed in six children, and one case showed remarkable findings. Coinfection with metapneumovirus was detected in the patient with the most severe course; Bordetella pertussis was detected in another patient. Seven patients required oxygen therapy. Albuterol was administered in four patients. One patient was admitted to the pediatric intensive care unit. Median length of admission was 4 days (range: 3-14). No patient died or showed any sequelae at discharge. Two patients developed recurrent bronchospasms. Conclusion: SARS-CoV-2 infection does not seem to be a main trigger of severe bronchiolitis, and children with this condition should be managed according to clinical practice guidelines. Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness) 4.090 JCR (2021) Q1, 21/130 Pediatrics 0.927 SJR (2021) Q1, 49/320 Pediatrics, Perinatology and Child Health No data IDR 2021 UEM

El vínculo humano-animal incluye componentes afectivos e implica bienestar para ambos participantes de la relación. Esto ha recibido apoyo reciente de la comunidad científica, destacando múltiples beneficios derivados para la salud humana. Sin embargo, sobrevive en la sociocultura una tendencia a patologizar la proximidad emocional con animales de compañía. Basándonos en las categorías psiquiátricas formales y desarrollos académicos, identificamos los trastornos mentales humanos desarrollados en el vínculo con animales. Estos incluyen: (1) Trastorno por acumulación de animales, (2) Trastorno de duelo complejo persistente por la pérdida de animales, (3) Trastorno de ansiedad por separación de los animales, y (4) Trastornos por atracción sexual hacia los animales. En ningún caso el exceso de afecto puede dar cuenta de su formación, sino que estos trastornos más bien dependen de características vinculares particulares. Se destaca la necesidad de investigación científica en psiquiatría sobre el vínculo humano-animal y se proponen estrategias de abordaje interdisciplinarias., O vínculo humano-animal inclui componentes afetivos e implica bem-estar para ambos os participantes. Isso recebeu apoio recente da comunidade científica, destacando vários benefícios derivados para a saúde humana. No entanto, uma tendência a patologizar a proximidade emocional com animais de companhia ainda sobrevive informalmente na sociocultura. Com base em categorias psiquiátricas formais e desenvolvimentos acadêmicos, identificamos transtornos mentais em humanos desenvolvidos em um vínculo com os animais. Estes incluem (1) Transtorno de acumulação de animais, (2) Transtorno de luto complexo persistente por perder animais, (3) Transtorno de ansiedade por separação de animais e (4) Transtornos de atração sexual por animais. Em nenhum deles o excesso de afeto pode ser responsável por sua formação; ao contrário, eles dependem de características de vínculos particulares. Destaca-se a necessidade de pesquisas científicas em psiquiatria sobre o vínculo humano-animal e propõe propostas estratégias de abordagem interdisciplinar., The human-animal bond includes affectionate components and implies wellbeing for both (relationship) participants. This has recently received support from the scientific community, which highlights several secondary benefits for human health. However, there persists informally in the socio-culture a tendency to pathologize the emotional closeness with companion animals. Based on formal psychiatric categories and academic developments, we identify human mental disorders appeared in the relationship with animals. These include: 1. Animal hoarding disorder, 2. Persistent complex bereavement disorder due to the loss of animals, 3. Animal separation anxiety disorder, 4. Sexual attraction towardsanimals disorder. In none of these the excess of affection accounts for their development, on the contrary, these depend rather on bonding characteristics. We highlight the need of scientific research in psychiatry on the human-animal bond and propose interdisciplinary approach strategies., Dossier: Interacciones humano-animal, Facultad de Psicología

BackgroundAn immune correlate of protection from SARS-CoV-2 infection is urgently needed.MethodsWe used an ongoing household cohort with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity. Sequencing was performed to determine circulating strains of SARS-CoV-2. We investigated the protection associated with seropositivity resulting from prior infection, the anti-spike antibody titers needed for protection, and we compared the severity of first and second infections.ResultsIn March 2021, 62.3% of the cohort was seropositive. After March 2021, gamma and delta variants predominated. Seropositivity was associated with 69.2% protection from any infection (95% CI: 60.7%-75.9%), with higher protection against moderate or severe infection (79.4%, 95% CI: 64.9%-87.9%). Anti-spike titers of 327 and 2,551 were associated with 50% and 80% protection from any infection; titers of 284 and 656 were sufficient for protection against moderate or severe disease. Second infections were less severe than first infections (Relative Risk (RR) of moderated or severe disease: 0.6, 95% CI: 0.38-0.98; RR of subclinical disease:1.9, 95% CI: 1.33-2.73).ConclusionsPrior infection-induced immunity is protective against infection when predominantly gamma and delta SARS-CoV-2 circulated. The protective antibody titers presented may be useful for vaccine policy and control measures. While second infections were somewhat less severe, they were not as mild as ideal. A strategy involving vaccination will be needed to ease the burden of the SARS-CoV-2 pandemic.

Dengue virus serotypes 1-4 (DENV1-4) and Zika virus (ZIKV) are mosquito-borne flaviviruses that induce both virus-specific and broadly-reactive antibodies. A first DENV infection is thought to induce antibodies that wane over two years to titers that can subsequently enhance severe dengue disease, causing large dengue epidemics. Secondary DENV infection with a different serotype is thought to induce stable, cross-serotype protective antibodies. Low dengue disease incidence following the recent Zika pandemic led to the hypothesis that ZIKV infection is also transiently cross-protective. We investigated antibody kinetics in 4189 children up to 11 years after one and multiple DENV and ZIKV infections in longitudinal cohorts in Nicaragua. We used a DENV inhibition enzyme linked immunosorbent assay (iELISA), which measures antibodies associated with protection against dengue and Zika disease and with enhancement of dengue disease severity. Surprisingly, we found that overall DENV iELISA titers stabilized by 8 months post-primary DENV infection to a half-life longer than a human life and waned, although gradually, after secondary DENV infection. Similarly, DENV iELISA titers were stable or rose after primary ZIKV infection but declined in individuals with histories of DENV and ZIKV infection. In contrast, kinetics of anti-ZIKV antibodies post-ZIKV infection were similar regardless of prior DENV immunity. We observed heterogeneity in DENV iELISA titer, suggesting that individual antibody titer setpoint, rather than waning, is important for future dengue disease risk. Together, these findings change our understanding of anti-flavivirus antibody kinetics and have implications for measuring vaccine efficacy and for predicting future dengue and Zika outbreaks.

Specialized ommatidia harboring polarization-sensitive photoreceptors exist in the ‘dorsal rim area’ (DRA) of virtually all insects. Although downstream elements have been described both anatomically and physiologically throughout the optic lobes and the central brain of different species, little is known about their cellular and synaptic adaptations and how these shape their functional role in polarization vision. We have previously shown that in the DRA of Drosophila melanogaster, two distinct types of modality-specific ‘distal medulla’ cell types (Dm-DRA1 and Dm-DRA2) are post-synaptic to long visual fiber photoreceptors R7 and R8, respectively. Here we describe additional neuronal elements in the medulla neuropil that manifest modality-specific differences in the DRA region, including DRA-specific neuronal morphology, as well as differences in the structure of pre- or post-synaptic membranes. Furthermore, we show that certain cell types (medulla tangential cells and octopaminergic neuromodulatory cells) specifically avoid contacts with polarization-sensitive photoreceptors. Finally, while certain transmedullary cells are specifically absent from DRA medulla columns, other subtypes show specific wiring differences while still connecting the DRA to the lobula complex, as previously been described in larger insects. This hints towards a complex circuit architecture with more than one pathway connecting polarization-sensitive DRA photoreceptors with the central brain.

Glial cells form part of the neural stem cell niche and express a wide variety of ion channels; however, the contribution of these channels to nervous system development is poorly understood. We explored the function of the Drosophila ClC‐a chloride channel, since its mammalian ortholog CLCN2 is expressed in glial cells, and defective channel function results in leukodystrophies, which in humans are accompanied by cognitive impairment. We found that ClC‐a was expressed in the niche in cortex glia, which are closely associated with neurogenic tissues. Characterization of loss‐of‐function ClC‐a mutants revealed that these animals had smaller brains and widespread wiring defects. We showed that ClC‐a is required in cortex glia for neurogenesis in neuroepithelia and neuroblasts, and identified defects in a neuroblast lineage that generates guidepost glial cells essential for photoreceptor axon guidance. We propose that glia‐mediated ionic homeostasis could nonautonomously affect neurogenesis, and consequently, the correct assembly of neural circuits., Main Points ClC‐a chloride channel is expressed in glia of the stem cell niche and regulates neurogenesis in a non‐autonomous fashion. ClC‐a mutants have reduced neurogenesis, and consequently, smaller brains.ClC‐a mutants also display wiring defects.

Background Copy Number Alterations (CNAs) represent changes in the copy number of genomic segments of somatic cells due to chromosomal instability. CNAs include gene amplifications or deletions and can be involved in tumorigenesis. We analyzed CNAs data in pre- and post-treatment (ttm) tumors from patients (pts) with early breast cancer (BC) in the neoadjuvant trials GEICAM/2006-03 and GEICAM/2006-14, with the aim to identify CNAs in particular genomic regions (genetic entropy) associated with treatment response. Methods GEICAM/2006-03 (NCT00432172) HER2-negative pts were selectively treated according to clinical subtypes: triple negative (TN) pts were treated with standard anthracycline/taxane -based chemotherapy (AT-CT) +/- carboplatin, while luminal patients were randomized to AT-CT vs. hormonotherapy; GEICAM/2006-14 (NCT00841828) HER2+ pts received AT-CT plus anti-HER2 therapy.Shallow-whole genome Illumina sequencing DNA data from 204 paraffin-embedded tumors (100 pre- and 104 post-ttm) were segmented to obtain CNAs and recurrent altered genomic regions were defined. We used Wilcoxon test to analyze the frequency of altered regions and logistic regression analyses to explore their association with tumor response, in terms of pathological complete response (pCR) in breast and axilla. Validation of altered genes associated with therapy response was performed in the microarray gene expression-based Hatzis dataset (GSE25066) from pts receiving neoadjuvant AT-CT (1). Results A total of 672 regions covering the whole genome were identified upon analysis of CNAs data. Regions were categorized according to their alteration status as amplified, normal and lost. Comparative analysis of alterations revealed 11 regions significantly different (p Conclusions According to our results, neoadjuvant therapy can modulate genomic aberrations landscape in BC. Our data suggest that amplification of specific genes in the genomic locus (21q22.12) is involved in the neoadjuvant therapy response in early BC. (1): Hatzis et al., JAMA 2011, 305(18) 1873-81 Citation Format: Alba E, Rueda OM, Lluch A, Albanell J, Chin S-F, Chacón JI, Calvo L, De la Haba-Rodriguez J, Bermejo B, Ribelles N, Sánchez-Rovira P, Plazaola A, Barnadas A, Cirauqul B, Ramos M, Arcusa A, Carrasco E, Herranz J, Chiesa M, Caballero R, Santonja A, Rojo F, Caldas C. Genome copy number entropy as predictor of response for neoadjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-03.

Background There are few data on the full spectrum of disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across the lifespan from community-based or nonclinical settings. Methods We followed 2338 people in Managua, Nicaragua, aged, A community-based cohort in Managua, Nicaragua, had very high severe acute respiratory syndrome coronavirus 2 seropositivity but lower-than-expected severity. Overall, 69% of infections were asymptomatic or subclinical and 1.1% of infections were severe. Seropositivity was associated with 93.6% protection from symptomatic reinfection through March 2021.

Background: Hyperthermia (HT) therapy still remains relatively unknown, in terms of both its biological and therapeutic effects. This work aims to analyze the effects of exposure to HT, such as that required in anti-tumor magnetic hyperthermia therapies, using metabolomic and serum parameters routinely analyzed in clinical practice. Methods: WAG/RigHsd rats were assigned to the different experimental groups needed to emulate all of the procedures involved in the treatment of liver metastases by HT. Twelve hours or ten days after the electromagnetic HT (606 kHz and 14 kA/m during 21 min), blood samples were retrieved and liver samples were obtained. 1H-nuclear-magnetic-resonance spectroscopy (1H-NMR) was used to search for possible diagnostic biomarkers of HT effects on the rat liver tissue. All of the data obtained from the hydrophilic fraction of the tissues were analyzed and modeled using chemometric tools. Results: Hepatic enzyme levels were significantly increased in animals that underwent hyperthermia after 12 h, but 10 d later they could not be detected anymore. The metabolomic profile (main metabolic differences were found in phosphatidylcholine, taurine, glucose, lactate and pyruvate, among others) also showed that the therapy significantly altered metabolism in the liver within 12 h (with two different patterns), however, those changes reverted to a control-profile pattern after 10 days. Conclusions: Magnetic hyperthermia could be considered as a safe therapy to treat liver metastases, since it does not induce irreversible physiological changes after application.

Uterine fibroids are frequently encountered in gynecology and are a therapeutic challenge. New therapies, such as ulipristal acetate, could help with symptomatic relief, improve quality of life, and decrease uterine fibroid size. Notwithstanding, there is controversy about adverse effects, especially for hepatotoxicity.We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis, and generated a summary of findings table using the GRADE approach.We identified nine systematic reviews and included ten studies overall, of which five were randomized trials. We conclude that ulipristal increases the likelihood of amenorrhea, improves the quality of life, and decreases menstrual bleeding. However, there is also a likely increase in the risk of adverse effects. Furthermore, ulipristal could decrease the size of fibroids.Los miomas uterinos son una patología frecuente en ginecología, que tiene como desafío el enfrentamiento terapéutico. Existen nuevas terapias como el uso de acetato de ulipristal que podrían ayudar con el alivio sintomático y mejoría de la calidad de vida, además de la disminución del tamaño de los miomas uterinos. No obstante, existe controversia respecto a los efectos adversos, especialmente frente a la hepatotoxicidad.Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el tamizaje de múltiples fuentes de información, incluyendo MEDLINE/PubMed, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.Identificamos nueve revisiones sistemáticas que incluyeron diez estudios primarios, de los cuales cinco son ensayos aleatorizados. Concluimos que el uso de ulipristal aumenta la probabilidad de amenorrea, mejora la calidad de vida y disminuye el sangrado menstrual. Además, el uso de ulipristal podría disminuir el tamaño de los miomas. Sin embargo, podría aumentar el riesgo de efectos adversos.

Background: In recent years, tropical countries have faced consecutive explosive epidemics of chikungunya, Zika, and now COVID-19, each of which have featured large proportions of subclinical infections. Spatial studies of epidemics typically use case-only datasets to estimate incidence rates (cases/total population), often misinterpreting them as infection risks (infections/total population) or disease risks (cases/infected population). Methods: We examined these three measures in a pediatric cohort (N≈3,000) over two chikungunya epidemics and one Zika epidemic and in a household cohort (N=1,793) over one COVID-19 epidemic in Nicaragua. We used generalized additive models, the intra-cluster correlation coefficient, cluster detection analyses, geostatistical models, and spatiotemporal models to characterize the spatial epidemiology of each epidemic and examine the limitations of the case-only incidence rate. Results: Across analyses and all epidemics, case-based incidence rates considerably underestimated both infection and disease risks, resulting in a high and spatially non-uniform degree of bias. The spatial infection risk differed from the spatial disease risk, showing that areas with many infections did not necessarily have many cases. Typical case-only approaches precluded a full understanding of the spatial contours of immunity. Standard incidence cluster analyses unpredictably resembled either clusters of infection or disease risk across all epidemics. Spatiotemporal modeling of disease incidence revealed less pronounced dynamics than spatiotemporal modeling of infection risk. Interpretation: During epidemics of pathogens that cause large numbers of subclinical infections, misinterpreting incidence rates, as is common, results in substantial bias, a general finding applicable to many pathogens of high human concern. Funding Information: This study was supported by grants R01 AI099631 (AB), P01 AI106695 (EH), R01 AI120997 (AG), and U19 AI118610 (EH) from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Institutes of Health Centers of Excellence for Influenza Research and Surveillance [contract: HHS 272201400006C (AG)]; and the Open Philanthropy Project Fund for the production of recombinant SARS-CoV-2 spike protein, its receptor binding domain, and antibodies at the University of Michigan Center for Structural Biology. FBC was partially supported by a supplement to grant P01 AI106695. Declaration of Interests: Authors declare that they have no competing interests. Ethics Approval Statement: The Pediatric Dengue Cohort Study (PDCS) was approved by Institutional Review Boards of the University of California, Berkeley, the University of Michigan, Ann Arbor, and the Nicaraguan Ministry of Health. The Household Influenza Cohort Study (HICS) was approved by the University of Michigan, Ann Arbor and the Nicaraguan Ministry of Health. Participants’ parents or legal guardians provided written informed consent. Subjects six years and older provided verbal assent.

The spectral vegetation indices (VIs) are widely used in ecology and ecosystem modelling to study carbon uptake and plant responses to climate change. VIs can potentially be used the learn about ecosystem processes at the large scale and used to inform and constrain mechanistic understanding and models. Key VIs such as Normalized Difference Vegetation Index (NDVI) reflects the chlorophyll contents, biomass, and canopy structural changes. The Photochemical Reflectance Index (PRI) and the Chlorophyll Carotenoid Index (CCI) relate to photosynthetic light-use efficiency (LUE) and also capture longer-term pigment changes of the vegetation at leaf and canopy scales, particularly for evergreen species. The Near-Infrared Reflectance of the vegetation (NIRv) relates to the canopy structure. The Water Index (WI) provides leaf water content information. However, the factors that control the seasonal changes of these VIs at different spatial-temporal scales is unclear, hence the question of whether VIs can successfully be scaled from leaf to satellite level remains to be answered. The main objective of this study is to examine, how and why the key VIs (NDVI, PRI, CCI, NIRv and WI etc.) change at the seasonal scale across leaf, ecosystem and satellite data. We use leaf-level measurements, continuous ecosystem observations and satellite data (atmospheric corrected MODIS products-MAIAC) across the spring recovery period of Scots pine (two years data) and Norway spruce (one year data) in a boreal site in Finland to answer: (1) how do VIs change during the photosynthetic spring recovery of the vegetation at leaf, ecosystem and satellite scales? (2) How do environmental and bio-physiological factors affect the seasonal dynamics of VIs? (3) do the main affecting factors change between canopy position and species? (4) whether the main factors change between spatial scales? Our preliminary results show that at the leaf level of Scots pine, both PRI and CCI are more strongly correlated with LUE at top-canopy (r = 0.92 and 0.93, respectively) than at low-canopy (r = 0.63 and 0.72) positions. At the leaf level in Norway spruce, only top-canopy PRI and CCI are significantly correlated with LUE (r > 0.75). When focusing on the correlations with PRI and CCI with pigments, we found that in Scots pine needles and for both top and low canopy, more than 80% of variation in PRI and CCI are explained by Car/Chl ratio and de-epoxidation state of xanthophyll cycle pigments (DEPS), respectively. However, in spruce for both canopy positions, the strongest correlation with PRI and CCI is lutein/Chl ratio (r is between -0.97 and -0.85), respectively), followed by Car/Chl ratio (r is between -0.84 and -0.72). At the ecosystem level, the PRI is correlated with GPP (gross primary productivity) when winter data and low PAR (−2 s−1) is not considered (r = 0.63). The other VIs are under investigation and will also be presented. As a tentative conclusion, although optical properties covary with photosynthesis, mechanisms of variation appear species and light environment specific.

Plants that are tolerant of extreme low temperatures, and plants that are tolerant of desiccation, face similar physiological challenges, as low temperatures often result in extracellular ice formation resulting in desiccation of cells. Desiccation due to either low temperatures or water loss leads to severe mechanical as well as oxidative stress, and plants tolerant to either low temperatures or desiccation utilize similar mechanisms to cope with the extreme stress. Key mechanisms to cope with the mechanical stressors associated with cellular crowding include accumulation of both non-reducing sugars as well as LEA proteins. Key mechanisms to cope with oxidative stress include increases in (or the ability to maintain) antioxidant capacity, as well as increased usage of thermal energy dissipation. During both stressors major reductions in photochemical efficiency are observed that correlate with dark retention of the xanthophyll pigments zeaxanthin and antheraxanthin, suggesting sustained forms of thermal energy dissipation persist in these extreme stress scenarios to cope with the increased excitation pressure. The focus of this review is to highlight the shared physiological mechanisms used in both stress scenarios, with a focus on the mechanisms of photoprotection.

In 2015, a Zika epidemic in Brazil began spreading throughout the Americas. Zika virus (ZIKV) entered Managua, Nicaragua, in January 2016 and caused an epidemic that peaked in July–September 2016. ZIKV seropositivity was estimated among participants of pediatric (n = 3,740) and household (n = 2,147) cohort studies, including an adult-only subset from the household cohort (n = 1,074), in Managua. Seropositivity was based on a highly sensitive and specific assay, the Zika NS1 blockade-of-binding ELISA, which can be used in dengue-endemic populations. Overall seropositivity for the pediatric (ages 2–14), household (ages 2–80), and adult (ages 15–80) cohorts was 36, 46, and 56%, respectively. Trend, risk factor, and contour mapping analyses demonstrated that ZIKV seroprevalence increased nonlinearly with age and that body surface area was statistically associated with increasing seroprevalence in children. ZIKV seropositivity was higher in females than in males across almost all ages, with adjusted prevalence ratios in children and adults of 1.11 (95% CI: 1.02–1.21) and 1.14 (95% CI: 1.01–1.28), respectively. No household-level risk factors were statistically significant in multivariate analyses. A spatial analysis revealed a 10–15% difference in the risk of ZIKV infections across our 3-km-wide study site, suggesting that ZIKV infection risk varies at small spatial scales. To our knowledge, this is the largest ZIKV seroprevalence study reported in the Americas, and the only one in Central America and in children to date. It reveals a high level of immunity against ZIKV in Managua as a result of the 2016 epidemic, making a second large Zika epidemic unlikely in the near future.

Purificación Martínez del Prado,1 Isabel Alvarez-López,2,3 Severina Domínguez-Fernández,4 Arrate Plazaola,5 Oliver Ibarrondo,6 Elena Galve-Calvo,1 Nerea Ancizar-Lizarraga,2,3 María Gutierrez-Toribio,4 Ainhara Lahuerta-Martínez,5 Javier Mar6,7 1Medical Oncology Service, Basurto University Hospital, Bilbao, Spain; 2Medical Oncology Service, Donostia University Hospital, Donostia-San Sebastián, Spain; 3Biodonostia Health Research Institute, Donostia-San Sebastián, Spain; 4Medical Oncology Service, Araba University Hospital, Vitoria-Gasteiz, Spain; 5Medical Oncology Service, Onkologikoa, Donostia-San Sebastián, Spain; 6AP-OSI Research Unit, Alto Deba Integrated Health Care Organization, Mondragon, Spain; 7Health Services Research on Chronic Patients Network, Kronikgune Group, Bilbao, Spain Purpose: The 21-gene recurrence score (RS) is a genomic test developed as a prognostic and predictive tool to improve the treatment decision making in cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer. This study examined the clinical and economic impact of its use in 4 Basque Country university hospitals. Methods: Taking into consideration the RS result, we recorded the recommended initial systemic adjuvant therapy (endocrine therapy with or without chemotherapy) according to standard clinicopathologic factors and the final decision about chemotherapy. Then, if the RS was high, chemotherapy was recommended; it was not recommended if the RS was low; for those with an intermediate RS, clinicopathologic factors were considered, and the initial recommendation based on those factors was maintained. In addition, the probability of switching treatment was calculated. Then, we developed an economic evaluation by measuring the treatment’s incremental short-term budget impact from both the societal perspective and that of the Basque Health System. Patients’ characteristics and chemotherapy use were analyzed using logistic regressions and receiver operating characteristic curves. Results: Without an RS, chemotherapy would have been prescribed to 56% of 401 patients, but, with RS use, that percentage decreased to 25. The overall rate of decision change was 35.4%. Test inclusion led to a reduction in chemotherapy costs of €922 per patient in the total population. Although this reduction did not entirely offset the cost of the test, the productivity loss per patient was reduced by €1,977. Conclusion: The 21-gene RS test significantly changed the indication for chemotherapy. As chemotherapy treatments with no benefit were avoided, patients’ quality of life was improved. The short-term economic impact was negative for the Basque Health Service, but savings resulted when sick-leave costs were included. Keywords: early-stage breast cancer, adjuvant chemotherapy, 21-gene assay, economic evaluation, health care costs

Background Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) disease. Materials and methods Women with ER+, HER2-, stage II-III BC were treated preoperatively with four cycles of weekly nab-Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. Results Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%-38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%-34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%-13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine-rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009-0.689; p = .0216). Conclusion Despite failing to confirm an RCB III rate ≤16% in nab-Paclitaxel-treated patients, the RCB 0+I rate indicates a significant drug antitumor activity with low rates of grade 3-4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011-004476-10; ClinicalTrials.gov: NCT01565499). Implications for practice The pathological response rate (residual cancer burden [RCB]; Symmans criteria) of nanoparticle albumin-bound paclitaxel administered as neoadjuvant treatment for early estrogen receptor-positive, human epidermal growth factor receptor 2-negative disease was evaluated. Whereas poor response (RCB III) was 24.7%, similar to that for docetaxel, good response (RCB 0+I) reached 23.0%, far superior to the 13% for docetaxel, while keeping toxicity low. Exploratory biomarker analysis suggests secreted protein, acidic, cysteine-rich overexpression in tumor cells as a potential predictor of complete response (RCB 0). Findings point to an encouraging single-agent neoadjuvant treatment with low toxicity, which warrants future research and development.

Malaria is a disease that affects the world, caused by the parasite Plasmodium which resistance is emerging to medications that usually control it. Therefore, it is essential to seek alternative treatments like this one, our multidisciplinary work pursues, a variable radiofrequency energy at 2.45GHz to decrease the growth of parasitemia in blood. Experiments are carried on in vitro samples of blood infected with Plasmodium falciparum radiated in a microwave cavity controlling the rise of the temperature. The thermal properties of samples infected at different stages of the parasite are analyzed separately without using microwave radiation for thermal characterization. The energy absorbed by the infected sample is estimated using the specific heat of blood with Plasmodium falciparum. For thermo energetic control, radiation is applied in different duty cycles for a determined amount of energy observing an alteration which it is accentuated in energy radiation with more duty cycles and less power in watts. Our preliminary results show that thermo-energetic control system produce alterations in the growth of parasitemia levels. Furthermore, we confirm that using microwave radiation has a negative effect in the growth of Plasmodium falciparum. There is also, an increment of the specific heat as the parasitemia percentage increase in late stage parasites because in schizonts the Plasmodium falciparum changes the biophysical properties of the red blood cell. This thermo-energetic characterization could be transferred to in vivo samples, with the necessary adjustments for future applications.

In the fly optic lobe ∼800 highly stereotypical columnar microcircuits are arranged retinotopically to process visual information. Differences in cellular composition and synaptic connectivity within functionally specialized columns remains largely unknown. Here we describe the cellular and synaptic architecture in medulla columns located downstream of photoreceptors in the ‘dorsal rim area’ (DRA), where linearly polarized skylight is detected for guiding orientation responses. We show that only in DRA medulla columns, both R7 and R8 photoreceptors target to the bona fide R7 target layer where they form connections with previously uncharacterized, modality-specific Dm neurons: Two morphologically distinct DRA-specific cell types (termed Dm-DRA1 and Dm-DRA2) stratify in separate sublayers and exclusively contact polarization-sensitive DRA inputs, while avoiding overlaps with color-sensitive Dm8 cells. Using the activity-dependent GRASP and trans-Tango techniques, we confirm that DRA R7 cells are synaptically connected to Dm-DRA1, whereas DRA R8 form synapses with Dm-DRA2. Finally, using live imaging of ingrowing pupal photoreceptor axons, we show that DRA R7 and R8 termini reach layer M6 sequentially, thus separating the establishment of different synaptic connectivity in time. We propose that a duplication of R7→Dm circuitry in DRA ommatidia serves as an ideal adaptation for detecting linearly polarized skylight using orthogonal e-vector analyzers.

Summary Background Paedeatric Zika remains an understudied topic. WHO and the Pan American Health Organization (PAHO) Zika case definitions have not been assessed in children. We aimed to characterise clinical profiles and evaluate the diagnostic performance of the WHO and PAHO case definitions in a large cohort of paediatric Zika cases. Methods From January, 2016 to February, 2017, encompassing the major 2016 Zika epidemic, participants in the Pediatric Dengue Cohort Study (PDCS) in Managua, Nicaragua, were encouraged to visit the study health centre at first indication of any illness. PDCS participants were aged 2–14 years, healthy at enrolment, and recruited before the initiation of the present study. Molecular and serological assays were used to test participants exhibiting any of four broad clinical profiles suspected of resulting from a symptomatic Zika virus infection. These clinical profiles were: fever and at least two of headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations, and leukopenia; fever and at least two of nausea or vomiting, rash, aches and pains, positive tourniquet test, leukopenia, and any dengue warning sign; undifferentiated fever without evident cause, with or without any other clinical finding; and afebrile rash with or without any other clinical finding. We characterised acute clinical findings (signs, symptoms, and complete blood counts) in both Zika cases and non-Zika cases. Findings We prospectively followed a cohort of about 3700 children, of which 1110 were deemed eligible for inclusion. Four participants with laboratory-confirmed Zika (three co-infections with dengue virus, one missing complete blood count data) and two participants who were non-Zika cases (missing complete blood count data) were excluded from analysis. We analysed 556 laboratory-confirmed Zika and 548 non-Zika cases. The WHO case definition captured 176 confirmed Zika cases, and the PAHO definition 109 confirmed Zika cases, who presented with the most clinical findings and a dengue-like clinical profile. The remaining two thirds of Zika cases, principally characterised by undifferentiated fever or afebrile rash, were missed. Among Zika cases, rash (n=440)—particularly generalised erythematous rash (n=334)—fever (n=333), leukopenia (n=217), and headache (n=203) were most common and peaked within 3 days of illness onset. The most common Zika presentation over the first week of illness was rash only (n=80). The sensitivity of Zika case definitions increased across paediatric age (from 11·3% to 56·1% for the WHO case definition and from 6·0% to 36·6% for the PAHO case definition), as the prevalence of most clinical findings (particularly arthralgia) increased with age, irrespective of previous dengue virus infection. Consequently, Zika manifested differently across paediatric age; older Zika cases presented with a dengue-like clinical profile while younger Zika cases presented with undifferentiated fever or afebrile rash. Interpretation We provide the most thorough description of paediatric Zika to date. Most paediatric Zika cases go undetected under the WHO and PAHO case definitions, suggesting that current standards for Zika case ascertainment require revision. Zika manifests with mild but differing clinical profiles across paediatric age, presenting major challenges to diagnosis, surveillance, and efforts to control future Zika epidemics. Funding US National Institutes of Health.

Background: Most of the studies on sychological distress in Spain have been conducted in small geographical areas or specific population groups. However, there are no studies that provide representative data for each Autonomous Community (AC). The objectives of this paper are to determine, both in Spain and in the AC, the prevalence of psychological distress, diagnosis, use of psychoactive medication, social support and self-perceived health, as well as to study the association between psychological distress and the rest of the variables. Methods: Cross-sectional study, using data from the 2006 National Health Survey, that was completed by 29,478 persons. Variables studied: sociodemographics, psychological distress (GHQ-12), self-perceived health, mental disorder diagnosis, functional social support (Duke) and use and prescription of psychoactive medication. Results: The prevalence of psychological distress in Spain was 20,1%; the highest prevalence was found in Canary Islands (28,2%) and the lowest in La Rioja (12,2%). Among those who presented psychological distress, 62,4% had never received a mental disorder diagnosis, and 71,6% had not used psychoactive medication in the last year. The highest prevalences of non-diagnosed cases (81,8%) and cases non-treated with psychoactive medication (83,1%) were found in La Rioja, whereas the lowest prevalences were found in Asturias. Eight percent of the persons who presented psychological distress had low social support and 63,8% reported bad self-perceived health. Conclusions: Psychological distress is a prevalent phenomenon, and more than half of the persons who suffer it receive neither a diagnosis nor psychoactive medication. Moreover, there are considerable differences between the AC. Yes Fundamentos: En España no existe ningún estudio en el que se hayan tomado muestras representativas por Comunidades Autónomas (CCAA) para estudiar la morbilidad psíquica. Los objetivos de este trabajo son describir su prevalencia, la presencia de diagnóstico, el consumo de psicofármacos, el apoyo social y la salud autopercibida y la relación entre la morbilidad psíquica y el resto de variables, tanto a nivel nacional como de CCAA. Método: Estudio transversal. Fuente de información: Encuesta Nacional de Salud 2006, muestra 29.478 personas. Variables estudiadas: sociodemográficas, morbilidad psíquica (GHQ-12), estado de salud autopercibido, diagnóstico de trastorno mental, apoyo social funcional (Duke) y consumo y prescripción de psicofármacos. Para determinar la frecuencia se utilizó el porcentaje y los intervalos de confianza al 95%. Para estudiar la relación entre morbilidad psíquica y el resto de variables se utilizó la prueba de Chi cuadrado, considerando la significación estadística con un valor de p

This work reports important advances in the study of magnetic nanoparticles (MNPs) related to their application in different research fields such as magnetic hyperthermia. Nanotherapy based on targeted nanoparticles could become an attractive alternative to conventional oncologic treatments as it allows a local heating in tumoral surroundings without damage to healthy tissue. RGD-peptide-conjugated MNPs have been designed to specifically target αVβ3 receptor-expressing cancer cells, being bound the RGD peptides by “click chemistry” due to its selectivity and applicability. The thermal decomposition of iron metallo-organic precursors yield homogeneous Fe3O4 nanoparticles that have been properly functionalized with RGD peptides, and the preparation of magnetic fluids has been achieved. The nanoparticles were characterized by transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), electron magnetic resonance (EMR) spectroscopy and magnetic hyperthermia. The nanoparticles present superparamagnetic behavior with very high magnetization values, which yield hyperthermia values above 500 W/g for magnetic fluids. These fluids have been administrated to rats, but instead of injecting MNP fluid directly into liver tumors, intravascular administration of MNPs in animals with induced colorectal tumors has been performed. Afterwards the animals were exposed to an alternating magnetic field in order to achieve hyperthermia. The evolution of an in vivo model has been described, resulting in a significant reduction in tumor viability.

Hymenophyllaceae is a desiccation tolerant family of Pteridophytes which are poikilohydric epiphytes. Their fronds are composed by a single layer of cells and lack true mesophyll cells and stomata. Although they are associated with humid and shady environments, their vertical distribution varies along the trunk of the host plant with some species inhabiting the drier sides with a higher irradiance. The aim of this work was to compare the structure and function of the photosynthetic apparatus during desiccation and rehydration in two species, Hymenophyllum dentatum and Hymenoglossum cruentum, isolated from a contrasting vertical distribution along the trunk of their hosts. Both species were subjected to desiccation and rehydration kinetics to analyze frond phenotypic plasticity, as well as the structure, composition and function of the photosynthetic apparatus. Minimal differences in photosynthetic pigments were observed upon dehydration. Measurements of ϕPSII (effective quantum yield of PSII), ϕNPQ (quantum yield of the regulated energy dissipation of PSII), ϕNO (quantum yield of non-regulated energy dissipation of PSII), and TL (thermoluminescence) indicate that both species convert a functional photochemical apparatus into a structure which exhibits maximum quenching capacity in the dehydrated state with minimal changes in photosynthetic pigments and polypeptide compositions. This dehydration-induced conversion in the photosynthetic apparatus is completely reversible upon rehydration. We conclude that H. dentatum and H. cruentum are homoiochlorophyllous with respect to desiccation stress and exhibited no correlation between inherent desiccation tolerance and the vertical distribution along the host tree trunk.

Sexual attraction towards animals disorder: Diagnostic classification based on a systematic review Abstract: Sexual intercourse between humans and animals has existed since the dawn of humanity in every place and culture of the world. Nevertheless, this issue has been scarcely approached by science. Given the wide differences in behavior and preferences among people who practice sex with animals, it is necessary to establish a subtypes classification. For this purpose, a systematic review of investigations was carried out that allowed us to select 26 empirical studies. Their analysis permitted to describe the group of Sexual Attraction Towards Animals disorder, comprising four differentiated disorders: (1) zoophilic disorder, (2) bestiality disorder, (3) sexual zoosadism, and (4) sexual attraction disorder towards animals due to medical or substance-induced illness. Additionally, the diagnostic criteria for each are proposed. Implications and limitations are discussed, as well as the value of having a classification of these disorders and the need to incorporate their study in the academic field. Keywords: Bestiality; disorders; paraphilias; zoophilia; zoosadism. Resumen: Las relaciones sexuales entre humanos y animales han existido desde los albores de la humanidad en todos los lugares y culturas del mundo. Sin embargo, han sido abordadas escasamente por la ciencia. Dadas las amplias diferencias en las conductas y preferencias entre quienes practican sexo con animales, se hace necesario establecer una clasificación de subtipos. Con ese propósito, se realizó una revisión sistemática de investigaciones que arrojó 26 estudios empíricos. El análisis de estos permitió describir el grupo de Trastornos por atracción sexual hacia animales, comprendiendo cuatro trastornos diferenciados: (1) trastorno zoofílico, (2) trastorno por bestialidad, (3) zoosadismo sexual, y (4) trastorno por atracción sexual hacia los animales debido a enfermedad médica o inducido por sustancias. Adicionalmente, se propusieron criterios diagnósticos para cada uno. Se discuten las implicancias y limitaciones, el valor de contar una clasificación de estos trastornos y la necesidad de incorporar su estudio en el ámbito académico. Palabras clave: Bestialismo; parafilias; trastornos; zoofilia; zoosadismo.

Glial cells form part of the neural stem cell niche and express a wide variety of ion channels; however, the contribution of these channels to nervous system development is poorly understood. We explored the function of the Drosophila ClC-a chloride channel, since its mammalian ortholog CLCN2 is expressed in glial cells, and defective channel function results in leukodystrophies, which in humans are accompanied by cognitive impairment. We found that ClC-a was expressed in the niche in cortex glia, which are closely associated with neurogenic tissues. Characterization of loss-of-function ClC-a mutants revealed that these animals had smaller brains and widespread wiring defects. We showed that ClC-a is required in cortex glia for neuroepithelia and neuroblast proliferation and identified defects in a neuroblast lineage that generates guidepost glial cells essential for photoreceptor axon guidance. We propose that glia-mediated ionic homeostasis could non-autonomously affect neurogenesis, and consequently, the correct assembly of neural circuits.

Zika virus (ZIKV) infection recently caused major epidemics in the Americas and is linked to congenital birth defects and Guillain-Barré Syndrome. A pilot study of ZIKV infection in Nicaraguan households was conducted from August 31 to October 21, 2016, in Managua, Nicaragua. We enrolled 33 laboratory-confirmed Zika index cases and their household members (109 contacts) and followed them on days 3–4, 6–7, 9–10, and 21, collecting serum/plasma, urine, and saliva specimens along with clinical, demographic, and socio-economic status information. Collected samples were processed by rRT-PCR to determine viral load (VL) and duration of detectable ZIKV RNA in human bodily fluids. At enrollment, 11 (10%) contacts were ZIKV rRT-PCR-positive and 23 (21%) were positive by IgM antibodies; 3 incident cases were detected during the study period. Twenty of 33 (61%) index households had contacts with ZIKV infection, with an average of 1.9 (range 1–6) positive contacts per household, and in 60% of these households, ≥50% of the members were positive for ZIKV infection. Analysis of clinical information allowed us to estimate the symptomatic to asymptomatic (S:A) ratio of 14:23 (1:1.6) among the contacts, finding 62% of the infections to be asymptomatic. The maximum number of days during which ZIKV RNA was detected was 7 days post-symptom onset in saliva and serum/plasma and 22 days in urine. Overall, VL levels in serum/plasma, saliva, and urine specimens were comparable, with means of 5.6, 5.3 and 4.5 log10 copies/ml respectively, with serum attaining the highest VL peak at 8.1 log10 copies/ml. Detecting ZIKV RNA in saliva over a similar time-period and level as in serum/plasma indicates that saliva could potentially serve as a more accessible diagnostic sample. Finding the majority of infections to be asymptomatic emphasizes the importance of silent ZIKV transmission and helps inform public health interventions in the region and globally., Author summary Zika virus (ZIKV) infection has become a major concern due to its association with congenital birth defects and Guillain-Barré Syndrome. We enrolled 33 laboratory-confirmed Zika cases (index cases) and their household members (109 contacts) in Managua, Nicaragua, and followed them for three weeks, collecting serum/plasma, urine and saliva specimens along with clinical, demographic, and socio-economic status information. We found that 61% of the index households had contacts with ZIKV infection, with an average of 1.9 (range 1–6) positive contacts per household, and in 60% of these households, ≥50% of the members were ZIKV-positive. Analysis of clinical information allowed estimating the symptomatic to asymptomatic (S:A) ratio of 14:23 (1:1.6) among the contacts. Finding 62% of the infections to be asymptomatic emphasizes the importance of silent transmission. Evaluating the maximum number of days during which ZIKV RNA was detectable showed that ZIKV was found up to 7 days post-symptom onset in serum/plasma and saliva and 22 days post-symptom onset in urine. Finding ZIKV RNA in saliva over a similar time period and concentration as serum/plasma indicates that saliva could potentially serve as a more accessible diagnostic sample. Overall, these data increase our understanding of ZIKV transmission and help inform public health interventions in the region and globally.

Background: The aim of this project was to provide an expert opinion regarding anti-human epidermal growth factor receptor 2 (HER2) therapy beyond second-line treatment of metastatic breast cancer (mBC). Methods: A group of experts discussed specific issues concerning anti-HER2 therapy in late-line settings in mBC. Results: Trastuzumab emtansine (T-DM1) or dual HER2 blockade appeared to be good options for HER2-positive mBC after ≥ 2 HER2-targeted therapies. Once an objective response has been achieved with anti-HER2-containing therapy, the anti-HER2 agent can be continued until progression of the disease, unacceptable toxicity or patient decision. mBC treated with ≥ 3 consecutive lines of anti-HER therapy, ≥ 1 being a dual HER2 blockade and with early progression of disease during a fourth or later-line treatment, are clinically resistant to anti-HER therapy. For progression of metastasis in the brain after anti-HER2 therapy, lapatinib and chemotherapy appear to be a good alternative after best local treatment. Conclusions: Further clinical trials are needed to provide valuable knowledge about the best treatment options in the later settings of mBC.

OBJECTIVE: To study the impact of intimate partner violence (IPV) on women's physical and psychological health. DESIGN: Cross-sectional study. SETTING:Primary care centers in 3 Andalusian provinces. PATIENTS: A total of 425 women, aged 18 to 65 years, were recruited following the same randomisation process in 6 primary care centers. MEASUREMENTS: A self-administered structured questionnaire for this study was used to gather the information. As well as sociodemographic variables, the instrument included questions about IPV, physical health indicators (chronic disease and type, lifetime surgeries, days in bed), psychological health (psychological morbidity, use of tranquilizers, antidepressants, pain killers, alcohol and recreational drugs), self-perceived health and social support. RESULTS: Of 425 women, 31.5% ever experienced any type of partner violence. Women experiencing IPV were more likely to suffer a chronic disease. IPV was significantly associated with a number of adverse health outcomes, including spending more than 7 days in bed in the last three months (ORa=2.96; CI 95%, 1.00-8.76), psychological morbidity (ORa=2.68; CI 95%, 1.60-4.49) and worse self-perceived health (ORa=1.89; CI 95%, 1.04-3.43), after controlling for potential confounding variables. CONCLUSION: This study shows that ever experiencing IPV is associated with a worse psychological and self-perceived health. Physical injuries are not the only "evidence" of the presence of IPV. Primary health care professionals are in a privileged position to help women who are abused by their partners. Objetivo. Estudiar el impacto en la salud física y psíquica de la violencia contra la mujer en la pareja. Diseño. Transversal. Emplazamiento. Centros de atención primaria de 3 provincias de la Comunidad Autónoma Andaluza. Participantes. Un total de 425 mujeres de entre 18 y 65 años asistentes a 6 centros. Se eligieron aleatoriamente siguiendo el mismo procedimiento en cada centro. Mediciones principales. Cuestionario estructurado autoadministrado que recoge, además de las variables sociodemográficas, variables relacionadas con el maltrato e indicadores de salud física (presencia de enfermedad crónica y tipo, intervenciones quirúrgicas a lo largo de la vida y días pasados en cama), psíquica (morbilidad psíquica, consumo de tranquilizantes, antidepresivos, analgésicos, alcohol y drogas no legales), salud autopercibida y apoyo social. Resultados. La frecuencia de maltrato fue del 31,5%. Las mujeres víctimas de maltrato presentaron mayor riesgo de padecer enfermedades crónicas. La asociación entre el maltrato y pasar más de 7 días en cama fue estadísticamente significativa (odds ratio [OR] = 2,96; intervalo de confianza [IC] del 95%, 1,00-8,76). El maltrato presentó una asociación significativa con la morbilidad psíquica (OR = 2,68; IC del 95%, 1,60-4,49) y con la salud autopercibida (OR = 1,89; IC del 95%, 1,04-3,43) tras ajustar por otras variables. Conclusiones. Los resultados de este trabajo muestran que el maltrato global se asocia con una peor salud psíquica y una peor salud autopercibida. Las lesiones físicas no son la única «prueba» de la existencia de violencia doméstica. Los profesionales de atención primaria pueden desempeñar un papel esencial para ayudar a las mujeres que sufren abusos de sus parejas Yes

Purpose Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. Patients and Methods Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m2, respectively, × four cycles), followed by docetaxel (100 mg/m2 × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m2, respectively, × four cycles), followed by capecitabine (1,250 mg/m2 twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). Results After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). Conclusion Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.

Chloroplast of green photosynthetic tissues in the Viridiplantae (monophyletic group that includes green algae and terrestrial plants) is characterised by a relatively conserved composition of pigments (Esteban et al. 2015). Leaves of virtually all plant species invariably contain chlorophyll (Chl) a and Chl b, and six carotenoids. Five of them are xanthophylls (carotenoids that contain oxygen): neoxanthin (Neo), lutein (Lut), violaxanthin (Vio), antheraxanthin (Ant) and zeaxanthin (Zea). The remaining carotenoid is a carotene (no oxygen in the molecule): β-carotene (β-Car). Additionally, certain taxa contain a second carotene: α-Car, which partially substitutes β-Car in some species under low light environment (Young and Britton 1989; Esteban and Garcia-Plazaola 2016). Some species phylogenetically unrelated also include lutein epoxide (Lx), a xanthophyll likewise related to shade acclimation (Matsubara et al. 2005; Esteban et al. 2009b). Regarding pigment concentration, in agreement with the relatively conserved composition of pigments across green photosynthetic organisms, and because the maximum Chl concentration per leaf is limited by specific and physiological constrains (Niinemets 2007), photosynthetic pigments are restricted within specific ranges of concentrations. Highly reliable ranges of pigment content for non-stressed plants that were obtained from two data-bases comprising more than 800 species can be found in (Esteban et al. 2015; Fernandez-Marin et al. 2017) (summarized as reference in Table 3.1).

© 2018 Lee et al. The ability to culture normal human mammary epithelial cells (HMEC) greatly facilitates experiments that seek to understand both normal mammary cell biology and the many differences between normal and abnormal human mammary epithelia. To maximize in vivo relevance, the primary cell culture conditions should maintain cells in states that resemble in vivo as much as possible. Towards this goal, we compared the properties of HMEC strains from two different reduction mammoplasty tissues that were grown in parallel using different media and culture conditions. Epithelial organoids were initiated into three different media: two commonly used serum-free-media, MCDB 170-type (e.g. MEGM) and WIT-P, and a low stress media, M87A. Growth, lineage heterogeneity, p16 protein expression, and population doublings to senescence were measured for each culture condition. MCDB 170 caused rapid senescence and loss of heterogeneity within 2 to 3 passages, but some cultures went through the 1 to 2 month process of selection to generate clonal finite post-selection poststasis cells. WIT-P caused impressive expansion of luminal cells in 2nd passage followed by their near complete disappearance by passage 4 and senescence shortly thereafter. M87A supported as much as twice the number of population doublings compared to either serumfree medium, and luminal and myoepithelial cells were present for as many as 8 passages. Thus, of the three media compared, WIT-P and MCDB 170 imposed rapid senescence and loss of lineage heterogeneity, phenotypes consistent with cells maintained in high-stress conditions, while M87A supported cultures that maintained multiple lineages and robust growth for up to 60 population doublings. In conjunction with previous studies examining the molecular properties of cultures grown in these media, we conclude that M87A medium is most able to support long-term culture of multiple lineages similar to in vivo conditions, thereby facilitating investigations of normal HMEC biology relevant to the mammary gland in situ.

The assembly of neural circuits relies on the accurate establishment of connections between synaptic partners. Precise wiring results from responses that neurons elicit to environmental cues and cell-cell contact events during development. A common design principle in both invertebrate and vertebrate adult nervous systems is the orderly array of columnar and layered synaptic units of certain neuropils. This similarity is particularly striking in the visual system, both at the structural and cell-type levels. Given the powerful genetic approaches and tools available in Drosophila, the fly visual system has been extensively used to probe how specific wiring patterns are achieved during development. In this review, we cover the developmental principles and molecular strategies that govern the assembly of columnar units (lamina cartridges and medulla columns), the formation of layers, afferent specific layer selection, and synaptogenesis in Drosophila. The mechanisms include: sequential developmental steps that ensure coordinated assembly of synaptic partners; anterograde and autocrine signaling; interactions between cell-surface molecules, or secreted molecules and their receptors that take place among neurons; and glia signaling to neurons.

Rooted cuttings of Eridano and I-214 Populus clones were treated in hydroponics with high [Zn] to establish their phytoextraction capacity and physiological responses for phytoremediation. The Bio-concentration factor, Uptake ratio and Translocation factor revealed that the highest Zn accumulation occurred in roots. Lower accumulation at 1 mM [Zn] in Eridano aerial parts limited Zn toxicity on photosynthetic machinery. Increasing [Zn] negatively affected growth, net photosynthesis, stomatal conductance, maximum quantum yield, chlorophyll content and hydric parameters. The physiological impairment in I-214 at 1 mM [Zn] indicated a greater sensitivity to high [Zn] than Eridano. At 5 mM [Zn], high toxicity for both clones occurred. Upregulation of photoprotective and antioxidant responses was a consequence of Zn stress rather than a Zn tolerance mechanism. Increased de-epoxidation state of the xanthophyll-cycle, α-Tocopherol and reduced glutathione and decreased total phenolics in I-214 at 1 mM [Zn] suggested that it responded earlier to oxidative stress when compared to Eridano.

Clinical Trial, Phase III; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy. Yes

Aims: nab-paclitaxel is an innovative chemotherapy that consists of nano-particles of human serum albumin bound paclitaxel. It exploits the role of albumin as the natural carrier of hydrophobic molecules in human to increase paclitaxel delivery to tumor cells. Weekly nab-paclitaxel showed a superior efficacy compared to every 3-weeks docetaxel in a randomized phase II study in metastatic breast cancer (Gradishar JCO 2009, Clin. Breast Cancer 2012). This single arm phase II trial has been designed to evaluate the activity and safety of weekly nab-paclitaxel as neoadjuvant treatment of early stage breast cancer patients with positive estrogen receptors and negative HER2. Methods: Stage II-III patients were included and treated with nab-paclitaxel weekly at a dose of 150 mg/m2 on days 1, 8 and 15 every 4 weeks for 4 cycles. Following chemotherapy, patients undergo surgery and adjuvant therapy (with radiation, chemo and endocrine therapy) under the investigator criteria. The primary objective is to determine the residual cancer burden class III as measured by the Symmans criteria (JCO 25:4422,2007). Secondary objectives include pathological complete response, overall response, invasive disease free survival, safety and potential correlative biomarkers. Results: Eighty-three patients have been recruited in the study in 13 Spanish institutions. Here we report safety data from 77 patients. Median age was 48 years, 62% were postmenopausal and 94% had ECOG PS 0; most patients were stage II (23% IIa and 36% IIb). A total of 259 cycles have been administered to date; 47 patients completed 4 cycles as planned, 5 patients discontinued treatment early (due to grade 2-3 sensory neuropathy in 4 patients), the remaining patients are still under treatment. The treatment was delayed in 8.1% of patients; nab-paclitaxel doses were omitted and reduced in 3.9% and 9.7% of cycles respectively, for a relative dose intensity of nab-paclitaxel of 97.3%. The most frequent reasons for dose modifications were neutropenia (5.4%) and neuropathy (2.7%). The main grade 2/3 adverse events are described in table 1. Table 1Related adverse events.Per patient (N = 74)Per Cycle (N = 259)NCI-CTCAE vs 4.0. (>5% grade 2-4)Grade 2, N (%)Grade 3, N (%)Grade 2, N (%)Grade 3, N (%)Leukopenia6 (8.1)1 (1.4)11 (4.2)1 (0.4)Neutropenia17(23)7 (9.5)30 (11.6)9 (3.5)Alopecia47(63.5)—121 (46.7)—Fatigue11 (14.9)2 (2.7)17 (6.6)2 (0.8)Neuropathy: Sensory17 (23)2 (2.7)25(9.6)5 (1.9)Musculoskeletal Pain11 (14.9)0 (0)13 (5.0)0 (0) Conclusions: Neoadjuvant therapy with weekly nab-paclitaxel at dose of 150 mg/m2 on days 1, 8 and 15 every 4 weeks was well tolerated. Final safety data for the entire treated patients will be mature and presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-15.

Desiccation-tolerant plants are able to withstand dehydration and resume normal metabolic functions upon rehydration. These plants can be dehydrated until their cytoplasm enters a ‘glassy state’ in which molecular mobility is severely reduced. In desiccation-tolerant seeds, longevity can be enhanced by drying and lowering storage temperature. In these conditions, they still deteriorate slowly, but it is not known if deteriorative processes include enzyme activity. The storage stability of photosynthetic organisms is less studied, and no reports are available on the glassy state in photosynthetic tissues. Here, the desiccation-tolerant moss Syntrichia ruralis was dehydrated at either 75% or

Purpose: Hormone receptor–positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified. Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2− disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors. Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine–sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy. Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035–44. ©2016 AACR.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

Studies have shown that some sociodemographic factors, such as marital status, employment status or social class, can affect mental health in different ways for each gender. However, up until now, few research projects have tried to ascertain if the role that reproductive work or psychosocial factors play in mental health is different for men and women. The aim of this study is to assess the differences between men and women in terms of how reproductive work, sociodemographic and psychosocial factors are linked to psychological distress in Spain. A cross-sectional study of 29,478 male and female adults using data gathered for the Spanish National Health Survey 2006 was carried out. Psychological distress was measured using the GHQ-12. The independent variables analyzed were: sociodemographic, psychosocial (family functionality and functional social support) and those related to reproductive work (living with or being in charge of different types of people needing care and number of hours devoted to caregiver tasks). Different independent logistic regression models were developed for men and women. In general, with the exception of men who were more prone to psychological distress if they were signed off work for 3 months or more, no major differences were observed regarding the effect of sociodemographic and psychosocial characteristics on psychological distress. With regard to reproductive work, the likelihood of psychological distress doubles in both sexes when the person lives with someone who needs care. In women, a greater number of hours devoted to caring for another person is associated with an increase in distress. Men play a less frequent role in caregiving, but the impact on psychological distress is similar to that in women. Women experienced more psychological distress when they had to live with or be in charge of a disabled person or different types of persons needing care, while men were not affected by this. Major differences have been identified in terms of psychological distress in women and men in several aspects of reproductive work to date unexplored.

This is a copy of an article published in the Jornal of Women's Health © 2009 [copyright Mary Ann Liebert, Inc.]; Journal of Womens Health is available online at: http://www.liebertpub.com/JWH Background: Partner violence against women is a major public health problem. Although there are currently a number of validated screening and diagnostic tools that can be used to evaluate this type of violence, such tools are not available in Spain. The aim of this study is to analyze the validity and reliability of the Spanish version of the Index of Spouse Abuse (ISA). Methods: A cross-sectional study was carried out in 2005 in two health centers in Granada, Spain, in 390 women between 18 and 70 years old. Analyses of the factorial structure, internal consistency, test-retest reliability, and construct validity were conducted. Cutoff points for each subscale were also defined. For the construct validity analysis, the SF-36 perceived general health dimension, the Rosenberg Self-Esteem Scale and the Goldberg 12-item General Health Questionnaire were included. Results: The psychometric analysis shows that the instrument has good internal consistency, reproducibility, and construct validity. Conclusions: The scale is useful for the analysis of partner violence against women in both a research setting and a healthcare setting Yes

Background Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting. Patients and Methods Patients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles followed by docetaxel 100 mg/m2 × 4 cycles [EC-T]) or HT (exemestane 25 mg daily × 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging. Results Ninety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT. Conclusions Luminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT.

Objective To use imaging and laboratory techniques to evaluate the vascular distribution of magnetofluid in a rat model of liver metastases. Material and methods The livers of 33 WAG/Rij Crl rats were seeded with CC-531 colorectal cancer cells. After we checked tumor development, 10 rats received hepatic intra-arterial infusions of Lipiodol ® with nanoparticles of Fe3O4 in suspension, and 5 were reserved as controls. Axial STIR (TR: 3600 ms/TE: 29 ms/TI: 130 ms) and gradient-echo (GE) (120/4 and 120/14) MRI sequences were acquired on a 1.5 T scanner. After necropsy, rats were classified into one of two stages according to tumor development: early ( 10 metastases, each >3 mm). Samples of liver and of metastases were taken from the 15 animals for quantification of iron concentrations by inductively coupled plasma mass spectrometry (ICPMS). The data were analyzed using nonparametric tests; values of p Results Five animals had early tumor development and five had advanced tumor development. In the GE sequences, early stage metastases showed homogeneous signal reduction attributable to the presence of magnetofluid. Spectrometry found significant differences between the iron concentration in rats with early stage metastases and controls ( p = 0.002) as well as between rats with early stage metastases and those with late stage metastases ( p = 0.001). The ratio of exogenous iron in metastases and in liver in early stage rats was 2.6:1. The concentration of exogenous iron in the liver was significantly different from that in tumors only in early stage animals ( p = 0.043). Conclusions MRI and spectrometry made it possible to evaluate the vascular distribution of magnetofluid in the liver and revealed the differences in its affinity for metastases in different stages of disease.

José J Echevarria-Uraga,1 Ignacio García-Alonso,2 Fernando Plazaola,3 Maite Insausti,3 Néstor Etxebarria,3 Alberto Saiz-López,4 Begoña Fernández-Ruanova51Radiology Department, Hospital de Galdakao-Usánsolo, Bizkaia, Spain; 2Experimental Surgery Laboratory, Medicine Faculty, University of the Basque Country, Bizkaia, Spain; 3Faculty of Science and Technology, University of the Basque Country, Bizkaia, Spain; 4Pathology Department, Hospital de Galdakao-Usánsolo, Bizkaia, Spain; 5Osatek SA Unidad del Hospital de Galdakao-Usánsolo, Bizkaia, SpainPurpose: To evaluate, in an experimental model, the reliability of MRI for determining whether a higher iron concentration was obtained in tumor tissue than in normal liver parenchyma after intra-arterial administration of Fe3O4 lipophilic nanoparticles.Materials and methods: WAG/RijCrl rats were inoculated in the left hepatic lobe with 25,000 syngeneic CC-531 colon adenocarcinoma cells, after which they were randomized into two groups: control (CG) and infused (IG). After confirming tumor induction, the IG rats received intra-arterial suspensions of Fe3O4 nanoparticles (2.6 mg) in Lipiodol® (0.15 mL). To calculate the iron concentration, [Fe], in the tumor and liver tissues of both groups of rats, measurements of signal intensity from the tumors, healthy liver tissue, and paravertebral muscles were made on a 1.5T MRI system in gradient-echo DP* and T2*-weighted sequences. In addition, samples were collected to quantify the [Fe] by inductively coupled plasma-mass spectrometry (ICP-MS), as well as for histological analysis. Statistical analysis was performed with non-parametric tests, and Bland–Altman plots were produced; P values

Background: To evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in stage II-III, previously untreated breast cancers (BC) patients (pts) in the context of a phase II, single-arm, multicenter and prospective clinical trial. To address this aim, we examined baseline and induced changes after a single bevacizumab administration as potential early predictors of response. Methods: Pts received a single infusion of bevacizumab (15 mg/kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/kg) every 21 days (C2-C5) following by surgery. Early assessment of tumor changes was performed by paired tumor-biopsies and MISO PET/CT before and 14–21 days after bevacizumab administration (C1). Biomarker expression was assessed by immunohistochemistry (IHC) (Ki67, CD31, CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) on formalin-fixed, paraffin-embedded tissue before and after bevacizumab infusion (C1). MISO SUV and tumor volume depicted by PET were calculated. Pathological response on surgical specimens was assessed according to Miller/Payne classification. Pts with tumor reduction >90% were considered as best responders (G4-G5) whether tumor reduction Results: This analysis was performed on the training set including 73 patients (49 yr, range 29–70). Twenty (27%) patients obtained best response (G4-G5) whether 50 (68%) were considered as no responder (G1-G2-G3). Response was associated with negative estrogen receptors expression (p=0.02) and high Ki67 basal and after C1 expression (p=0.009 and p=0.01). Six (54%) of triple negative tumors were responders (p=0.05). Interestingly, change in pVEGFR2 [Y951] staining induced by bevacizumab administration and basaline MISO tumor volume was found significantly associated with response (p=0.03 and 0.057). Decrease in the phosphorilation status of VEGFR2 (Y951) >70% yielded a receiver operating characteristic (ROC) curve area of 0.681 (95% CI: 0.536 — 0.825) with 84% sensitivity and 95% specificity. The positive and negative predictive values for this marker were 60% and 64%, respectively. The change in phosphorilation status of VEGFR2p remains a significant predictor biomarker of response in multivariate analysis (OR=0.9, IC%95 0.96−0.99, p=0.04) after adjusting for clinical-pathological characteristics. Conclusion: These findings underline the potential value of early decrease in phosphorilation status of VEGFR2 after bevacizumab infusion as predictive biomarker of response to anti-angiogenic therapy in breast cancer. Moreover, tumor hypoxic volume obtained by MISO might be associated with response. A validation set is warranted to confirm these findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-04.

Background: To investigate the hypothesis that early changes in tumor proliferation and hypoxic status induced by bevacizumab and assessed by imaging biomarkers might predict response to bevacizumab therapy. Methods: 73 chemotherapy naïve, stage II-III breast cancer (BC) patients (pts) were enrolled in the training set of this phase II, single-arm, multicenter and prospective clinical trial from October 2009 until November 2010. Pts received single infusion of bevacizumab (15 mg/kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/kg) every 21 days (C2-C5) following by surgery. Tumor proliferation and hypoxic status were evaluated using FLT and MISO PET/CT at baseline and 14–21 days after bevacizumab (C1). Standardized uptake values (SUV) for FLT and MISO and ratios to reference tissues, mediastinum (T/Me) or muscle (T/Mu), for MISO were calculated. Pathological response on surgical specimens was assessed according to Miller/Payne grading system. Pts with reduction in tumor cells >30% (G3-G4-G5) or 20% yielded a ROC curve area of 0.7 (95% CI: 0.56 - 0.85) with 94% sensitivity and 87% specificity. Conclusion: Bevacizumab determined a marked decrease in tumor proliferation. Interestingly, a decrease greater than 20% in tumor hypoxic status after C1 and assessed by MISO was found significantly associated with pathological response suggesting a potential value of early decrease in hypoxic tumor status as predictive biomarker of response. Bevacizumab, causing normalization of the tumor microvasculature, seems to potentiate the effect of cytotoxic agents on primary BC. A validation set is warranted to confirm these findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-02.

Purpose: To investigate the effect of bevacizumab infusion on vascular parameters assessed by dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging and to test their association with pathological response in primary breast cancer. Materials and Methods: 73 patients (median age, 47 ys; age range, 29–70 ys) with biopsy-proven, previously untreated, primary breast cancer were recruited from October 2009 to November 2010 in this phase II, multicenter and non-randomized clinical trial. Patients (pts) received single infusion of bevacizumab (15 mg/kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/kg) every 21 days (C2-C5) following by surgery. All pts underwent DCE-MR imaging before and 14–21 days after C1. Quantitative and semiquantitative kinetic parameters were calculated at baseline and after C1, including the volume transfer constant (K(trans)), which primarily reflects the wash-in of the contrast agent, the backflow rate contrant (K(ep)), extracellular volume fraction (V(e)) and the initial area under the gadolinium concentration-time curve over 60 seconds (IAUGC(60)). Changes in the DCE-MRI kinetic parameters K(trans), K(ep), V(e) and IAUGC(60) were calculated and Wilcoxon test was used to assess significant effects induced by bevacizumab on kinetic parameters. Pathological response on surgical specimens after C5 was assessed according to Miller and Payne classification. Pts with tumor reduction >30% were considered as responders (G3-G4-G5) whether tumor reduction Results: DCE-MRI was performed before (n=72) and after (n=71) C1. K(trans), K(ep), V(e) and IAUCG(60) values were significantly different at the baseline and after C1 (p Conclusion: Bevacizumab affects tumor vasculature, perfusion and permeability as showed by the significantly reduction in all kinetic vasculature parameters obtained in DCE-MR imaging after C1. However, in our population these changes were not associated with pathological response. On the other hand, backflow rate constant, K(ep), a perfusion-related parameter derived from DCE-MRI yielded after C1 major than 80, may be associated with higher pathological response with a specificity of 88% and sensitivity of 90%. Future studies are warranted to confirm these findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-08-05.