Search

La presente investigación tuvo como objetivo determinar la relación entre el trabajo infantil y los derechos del niño en el distrito de Carabayllo, según los colaboradores del Programa de Prevención y Erradicación del Trabajo Infantil de ese distrito - PPTI. La metodología utilizada en el presente estudio es cuantitativa, correlacional, de corte transversal, y no experimental. La población participante en la investigación estuvo conformada por un total de 70 colaboradores del PPTI de Carabayllo: autoridades, funcionarios, trabajadores de la municipalidad, operadores de instituciones del Estado y de la sociedad civil que forman parte del COMUDENA del distrito. La técnica utilizada para levantar la información en el presente estudio fue la aplicación de una encuesta. El instrumento fue un cuestionario diseñado teniendo en cuenta las variables, las dimensiones y los indicadores establecidos previamente. Fue validado por 7 expertos, que lo consideraron aplicable, y se determinó su confiabilidad ejecutando un piloto, aplicándolo a 30 personas con características similares a la población participante; luego de ello, el Alfa de Cronbach determinó una fuerte confiabilidad y una alta confiabilidad. El 78.6 % de los encuestados manifestaron que existe una alta incidencia de trabajo infantil en el distrito de Carabayllo. El 74.3% de los participantes manifestaron que las actividades laborales que realizan los niños son nocivas o peligrosas. El 77.1% señalaron que el acceso de los niños trabajadores a sus derechos es deficiente. Se concluyó que existe una correlación positiva considerable entre Trabajo Infantil y Derechos del Niño, siendo el coeficiente de correlación de Spearman .510, aceptándose la hipótesis alterna y rechazándose la hipótesis nula. Lima Norte Escuela de Posgrado Gestión de políticas públicas Biodiversidad, cambio climático y calidad ambiental Apoyo a la reducción de brechas y carencias en la educación en todos sus niveles Reducción de las desigualdades

This paper studies heat fluxes from contributors and mitigators of urban heat islands using thermal images and weather data. Thermal images were collected from an observatory operating on the rooftop of a building between November 2021 and April 2022. Over the same period, an automatic weather station network was used to measure weather conditions at several locations on a university campus in Singapore. From data collected by the observatory and the automatic weather station network, a method was developed to estimate the heat emitted by building facades, vegetation, and traffic. Before performing the analysis of urban heat fluxes, it was observed that the surface temperature collected from the observatory is sensitive to some variables. After the sensitivity analysis, thermal images were calibrated against measurements of the surface temperature in an outdoor environment. Finally, several contributors and mitigators of urban heat islands were analyzed from heat fluxes assessed with thermal images and weather data. According to thermal images collected by the rooftop observatory, concrete walls are an important contributor to urban heat islands due to the longwave radiation they emit at night. Vegetation, on the other hand, seems to be an effective mitigator because of latent heat fluxes generated by evapotranspiration. Traffic looks to be a negligible source of heat if considered over a small portion of a road. In the future, more efforts can be made to estimate the magnitude of the heat released by an air-conditioning system from thermal images.

670 Background: Pancreatic Ductal Adenocarcinoma (PDAC) has historically been an important diagnostic and therapeutic challenge. The multidisciplinary approach and new diagnostic techniques’ implementation have modified this process. Methods: We conducted a retrospective analysis based on clinical data of patients with PDAC between the years 2010 to 2021, analyzing the diagnosis and initial treatment evolution. Results: 673 patients between 2010-2021 with a suspected diagnosis of pancreatic adenocarcinoma were reviewed. Most of them were metastatic (n=362; 53.8%), followed by locally advanced unresectable (n=166; 24.7%) and resectable or borderline resectable (n=145; 21.5%). Regarding the pathological diagnosis, it was not possible in 62 patients (9.2%), varying over time from 21.2% in 2010-2012 to 1% in 2019-2021 (p

66 Background: Patients with mCRC harboring BRAF mutation have worse prognosis and poor outcomes. However, those who have resectable metastatic disease and undergo surgery may have better outcomes compared to those who do not. Differences in clinical characteristics are not well known and may be critical to identify patients with better prognosis. Methods: We performed a retrospective analysis of 299 patients with mCRC in a tumor registry from 2015 to 2021. We compared the clinical characteristics and survival trends of both cohorts (BRAF mutated and BRAF wild type). Furthermore, we analyzed clinical and survival features of 23 patients with BRAF mutated mCRC who received metastases resection. Results: We identified 34 patients with BRAF mutation (11.37%). Several characteristics were significantly more frequent in this group: age

159 Background: Peritoneal metastases in patients with mCRC are commonly associated with poor outcomes. Some of these patients are candidates to undergo metastases surgery, which may result in better prognosis; however, clinical and molecular characteristics of these patients remain uncertain. Methods: We conducted a retrospective analysis of 166 patients with mCRC and peritoneal metastases in a tumor registry from 2015 to 2021, analyzing the clinical and molecular characteristics, as well as progression-free survival (PFS) and overall survival (OS) of patients who received peritoneal surgery versus those who did not. Results: From the whole population, 65 patients (39%) underwent peritoneal metastases surgery, and several characteristics were more frequent in this subgroup: ECOG 0 (n = 26, OR 2.75, p = 0,0069), age

740 Background: Several inflammatory scores such as the Systemic Inflammation Response Index (SIRI), the Inflammation Index Score (IIS), and the Neutrophil Lymphocyte Ratio (NLR) have been reported to have prognostic value in PDAC with different results. We hypothesize that the KS, designed to predict the risk of cancer-associated thrombosis, may also be a surrogate marker for inflammation to be included as a relevant prognostic index for PDAC. Methods: Baseline characteristics and individual SIRI, IIS, NLR and KS indexes from 197 PDAC patients diagnosed in our center between 2019 and 2021 have been retrospectively recorded. PFS and OS (Log-rank test) have been used to compare the different scores of each index in the whole population as well as in the metastatic setting. Kruskal-Wallis test and Mann-Whitney test were also done to determine if the SIRI varies significantly between KRS values. Results: Of the 197 patients analyzed, 41 were resectable (20.8%), 54 locally advanced (27.4%) and 102 metastatic (51.8%). Patients with intermediate risk according to KS (2 points, n = 131, 66.5%) had a significantly higher median PFS (8.4 vs. 4.8 months, p = 0.03) and significantly higher OS (12.9 vs. 7.7 months, p = 0.002) than those with high-risk (> 3 points, n = 66, 33.5%). The median OS for patients with low (< 3,000) and high (> 3,000) SIRI was 13.1 and 9.3 months respectively (p = 0.05). No significant differences were observed in PFS. In the metastatic setting, a low SIRI was significantly associated with higher OS (10.6 vs. 5.8, p = 0.016). No significant differences were observed in patients with low vs. high IIS and NLR. The Kruskal-Wallis test indicates that SIRI values vary between at least two KS values (p < 0.001). The Mann-Whitney test found significant differences between the SIRI values from S 2 and 3 (p = 0.002) as well as 2 and 4 (p = 0.04). SIRI values were higher in patients with KRS > 3 vs. 2. Conclusions: This retrospective analysis showed that patients with lower KS live longer and progress later than those with higher KS. Lower SIRI is associated with better survival in metastatic patients, being on the verge of statistical significance in the whole cohort. There is a strong correlation between SIRI and KS. In this cohort of unselected PDAC patients, KS is a prognostic factor for OS and PFS that correlates with subclinical inflammation and demonstrates to be a better predictor than other inflammatory indexes that deserves further analysis.

The pro-inflammatory cytokine IL-6 has been associated with the progression of PCa to a castration-resistant phenotype. In this work, we characterized the biochemical changes evoked by IL-6 in three different models of PCa cells, including LNCaP, C4-2, and PC3. The effect of IL-6 on PCa cells was compared with the effect obtained by co-stimulation with the cAMP-inducing agent forskolin (FSK). Stimulation of LNCaP cells with IL-6 or IL-6 + FSK evoked increased expression of the neuroendocrine marker tubulin IIIβ and Cav3.2 T-type Ca

PURPOSE Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies. PATIENTS AND METHODS Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer. RESULTS Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor. CONCLUSION We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.

Objectives To evaluate the effectiveness of transcutaneous tibial nerve stimulation (TTNS) compared to percutaneous tibial nerve stimulation (PTNS) in sustaining symptom improvement over a 6-month period in women with idiopathic Overactive Bladder (OAB) who had responded to an initial 12-week course of PTNS. Design Randomized, active-controlled trial. Participants Twenty-four women diagnosed with idiopathic OAB successfully treated with PTNS were included in this study. Interventions Twelve subjects were allocated to receive monthly sessions of PTNS for six months, and twelve subjects followed a flexible home-based TTNS regime after instruction on the use of a TENS device for the same follow-up time. Outcomes Participants were assessed at six weeks, three months and six months after completing the initial course of PTNS. Primary outcomes were changes from baseline in urinary frequency, number of episodes of urgency and number of episodes of urge urinary incontinence (UUI). Subjectively reported severity of symptoms and quality of life (QoL) were assessed using the validated OAB questionnaire (OAB-q). Results Urinary frequency, episodes of urinary urgency and episodes of UUI did not change significantly between baseline and six months in either group. Similarly, OAB-q scores for severity of symptoms and QoL were maintained within both arms for the duration of the study. There were no statistically significant differences between the groups in any of the outcome measures at any of the study points. Conclusion TTNS is effective in the maintenance of symptom improvement in women with OAB who had positively responded to a course of 12 weekly PTNS sessions. The trial was registered in the Clinicaltrials.gov PRS database (Identifier: NCT02377765).

(100-120 words) Alterations in lipid metabolism are being increasingly implicated in the initiation, aggressiveness, and progression to metastasis of cancers. Recent advances have shown that high levels of fat availability and altered lipid metabolism can promote the metastatic process by: i) providing energy for cancer cells, thereby supporting invasion and colonization; ii) promoting their survival by enhancing anti-oxidative, anti-apoptotic mechanisms and therapy resistance; and iii) inhibiting the immune surveillance from detecting/removing tumor cells. These findings are especially disturbing given the alarmingly high fat intake within our modern diet. However, the reprogramming of fat metabolism exhibited by cancer cells and intratumor immune cells promises to generate new pharmacological opportunities to treat metastasis.

In this paper we present novel pulse clarity metrics based on different sections of a state-of-the-art beat tracking model. Said model consists of two sections: a recurrent neural network that estimates beat probabilities for audio and a dynamic Bayesian network (DBN) that determines beat moments from the neural network's output. We obtained pulse clarity metrics by analyzing periodical behavior from neuron activation values and we interpreted the probability distribution computed by the DBN as the model's certainty. To analyze whether the inner workings of the model provide new insight into pulse clarity, we also proposed reference metrics using the output of both networks. We evaluated the pulse clarity metrics over a wide range of stimulus types such as songs and mono-tonal rhythms, obtaining comparable results to previous models. These results suggest that adapting a model from a related task is feasible for the pulse clarity problem. Additionally, results of the evaluation of pulse clarity models on multiple datasets showed that, with some variability, both ours and previous work generalized well beyond their original training datasets.

Resumen Introduccion: Desde el inicio de la pandemia por COVID-19 se ha alertado sobre los efectos que esta tendria en la salud mental de la poblacion y se habia previsto un aumento de las tasas de suicidio como ocurrio en pandemias previas. Los estudios realizados hasta la fecha difieren respecto a si durante la pandemia por COVID se estan viendo afectadas las tasas de suicidio. Material y metodos: Se han incluido todos los individuos registrados por ideas o intentos de suicidio en el Codigo Riesgo Suicidio (CRS) que pertenecen a la ciudad de Barcelona desde el 01 de Enero de 2018 hasta el 30 de Junio de 2021. Se ha realizado un analisis bivariado entre el periodo 2018-2019 y el periodo de pandemia. Se ha calculado el crecimiento porcentual de la incidencia mensual de los casos de CRS, utilizando como referencia la media de la incidencia mensual del periodo 2018-2019. Resultados: Se registraron un total de 3388 consultas por ideas o intentos de suicidio. Se ha producido un incremento del 43,20% en la incidencia mensual de ideas e intentos de suicidio durante la pandemia en comparacion con el periodo 2018-2019, alcanzando un incremento maximo del 573.8% en menores de edad en el mes de mayo de 2021. Conclusiones: Durante el periodo de pandemia por COVID-19 se han incrementado las consultas por ideas e intentos de suicidio respecto a los 2 anos previos en la ciudad de Barcelona. Cabe destacar este crecimiento especialmente en menores de edad.

Despite the large number of patients with early breast cancer (EBC) who have been treated with capecitabine in randomised trials, no individual patient data meta-analysis has been conducted. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS), and the secondary objectives were to analyse distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and the interaction between capecitabine-related toxicity and treatment effect.www.gov and www.pubmed.ncbi.nlm.nih.gov were searched using the following criteria: use of capecitabine for EBC as adjuvant or neoadjuvant therapy; multicentre randomised trial with100 patients; recruitment completed, and outcomes available. Required data were available for 13 trials.Individual data from 15,993 patients were collected. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared with treatment without capecitabine (hazard ratio [HR] 0.952; 95% CI 0.895-1.012; P value = 0.115). There was also no effect on DFS in the subset of studies where capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; P = 0.455). However, capecitabine administered in addition to the standard systemic treatment improved DFS (HR 0.888; 95% CI 0.817-0.965; P = 0.005). An OS improvement was observed in the entire cohort (HR 0.892; 95% CI 0.824-0.965, P = 0.005) and in the subset of capecitabine addition (HR 0.837; 95% CI 0.751, 0.933, P = 0.001). Subgroup analyses revealed that triple-negative breast cancer (TNBC) patients benefitted from treatment with capecitabine overall and in addition to other systemic treatments in terms of DFS and OS.Capecitabine was able to improve DFS and OS in patients with TNBC and in all patients with EBC when administered in addition to systemic treatment.

Supplemental information can be found online at https://doi.org/10.1016/j.molcel.2022.10.005, ACKNOWLEDGMENTS P.A.-M was supported by a Marie Sklodowska-Curie Actions individual fellowship and the Beug Foundation. A.V. was supported by Fonds Wetenschappelijk Onderzoek (FWO Vlaanderen). J.E.-H. was supported by an MRC studentship. J.C.A was supported by a Cancer Research UK Career Development Fellowship (C47559/A16243). S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator grant agreement no. 771486–MetaRegulation, FWO Projects, Fonds Baillet Latour, KU Leuven- FTBO/Internal Funding, Stichting Tegen Kanker and the King Baudouin Foundation. Work in the A.J.F. group was supported by a Wellcome Trust-ISSF grant, funding from Barts Charity (MGU0404), and by a Cancer Research UK Centre Grant to Barts Cancer Institute (C355/A25137). The illustrations in the graphical abstract and Figure 5F were created using BioRender.com., Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis—the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability., Marie Sklodowska-Curie Actions, Beug Foundation, Fonds Wetenschappelijk Onderzoek (FWO Vlaanderen), Cancer Research UK Career Development Fellowship (C47559/A16243), European Research Council under the ERC Consolidator grant agreement no. 771486–MetaRegulation, FWO Projects, Fonds Baillet Latour, KU Leuven- FTBO/Internal Funding, Wellcome Trust-ISSF grant, Barts Charity (MGU0404), Cancer Research UK Centre Grant to Barts Cancer Institute (C355/A25137)

Background Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. Objective To compare the influence of distinctive trajectories of alcohol consumption throughout a woman's life on development of breast cancer (BC). Methods 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women's lifetime. Results Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (= 15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, >= 15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. Conclusions The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk., This study was funded by the Fundacion Cientifica Asociacion Espanola Contra el Cancer (AECC) (Scientific Foundation of the Spanish Association against Cancer 2006 & 2016) (Marina Pollan), Sociedad Espanola de Oncologia Medica (SEOM) (Spanish Society of Medical Oncology) (Miguel Martin), Scholarship 'Contrato de atraccion de talento' from Community of Madrid (Carolina Donat-Vargas), Fundacion Cerveza y Salud 2005 (Beer and Health Foundation 2005) (Miguel Martin) and Federacion de Asociaciones de Mujeres con Cancer de Mama (FECMA) (Spanish Federation of Associations of Women with Breast Cancer) (Miguel Martin, Marina Pollan).

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non‐pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first‐line phase III trials in HER2‐negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2‐negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms., SCOPUS: re.j, info:eu-repo/semantics/published

Purpose CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. Methods Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). Results Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. Conclusion Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2– ABC. Trial registration linicalTrials.gov NCT02941926.

It has been demonstrated that elamipretide (SS-31) rescues age-related functional deficits in the heart but the full set of mechanisms behind this have yet to be determined. We investigated the hypothesis that elamipretide influences post-translational modifications to heart proteins. The S-glutathionylation and phosphorylation proteomes of mouse hearts were analyzed using shotgun proteomics to assess the effects of aging on these post-translational modifications and the ability of the mitochondria-targeted drug elamipretide to reverse age-related changes. Aging led to an increase in oxidation of protein thiols demonstrated by increased S-glutathionylation of cysteine residues on proteins from Old (24 months old at the start of the study) mouse hearts compared to Young (5–6 months old). This shift in the oxidation state of the proteome was almost completely reversed by 8 weeks of treatment with elamipretide. Many of the significant changes that occurred were in proteins involved in mitochondrial or cardiac function. We also found changes in the mouse heart phosphoproteome that were associated with age, some of which were partially restored with elamipretide treatment. Parallel reaction monitoring of a subset of phosphorylation sites revealed that the unmodified peptide reporting for Myot S231 increased with age, but not its phosphorylated form and that both phosphorylated and unphosphorylated forms of the peptide covering cMyBP-C S307 increased, but that elamipretide treatment did not affect these changes. These results suggest that changes to thiol redox state and phosphorylation status are two ways in which age may affect mouse heart function, which can be restored by treatment with elamipretide. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00447-6.

"El presente trabajo muestra las actividades realizadas para la creación de una aplicación en realidad aumentada (AR) con fines de capacitación de un torno paralelo considerando el nivel I, implementada en un dispositivo móvil. En el nivel I de AR es necesario utilizar maracadores como medio de activación de los modelos 3D, por lo que se propuso utilizar descriptores clásicos (sift, surf, orb) para la extracción de caracteristicas de los marcadores."

Bladder cancer is the ninth most frequently diagnosed cancer worldwide, and there is a need to develop new biomarkers for staging and prognosis of this disease. Here we report that cell lines derived from low-grade and high-grade bladder cancers exhibit major differences in expression of glycans in surface glycoproteins. We analyzed protein glycosylation in three low-grade bladder cancer cell lines RT4 (grade-1-2), 5637 (grade-2), and SW780 (grade-1), and three high-grade bladder cancer cell lines J82COT (grade-3), T24 (grade-3) and TCCSUP (grade-4), with primary bladder epithelial cells, A/T/N, serving as a normal bladder cell control. Using a variety of approaches including flow cytometry, immunofluorescence, glycomics and gene expression analysis, we observed that the low-grade bladder cancer cell lines RT4, 5637 and SW780 express high levels of the fucosylated Lewis-X antigen (Lex, CD15) (Galβ1–4(Fucα1–3)GlcNAcβ1-R), while normal bladder epithelial A/T/N cells lack Lex expression. T24 and TCCSUP cells also lack Lex, whereas J82COT cells express low levels of Lex. Glycomics analyses revealed other major differences in fucosylation and sialylation of N-glycans between these cell types. O-glycans are highly differentiated, as RT4 cells synthesize core 2-based O-glycans that are lacking in the T24 cells. These differences in glycan expression correlated with differences in RNA expression levels of their cognate glycosyltransferases, including α1–3/4-fucosyltransferase genes. These major differences in glycan structures and gene expression profiles between low- and high-grade bladder cancer cells suggest that glycans and glycosyltransferases are candidate biomarkers for grading bladder cancers.

Myogenesis is a complex two-phase process of proliferation and differentiation, which seems to be greatly conserved in vertebrates. For the first time in fish, we identify the changes that occur in the proteome during this process in a gilthead sea bream (Sparus aurata) myocyte primary cell culture (on days 4, 8 and 12), using 2-D gel electrophoresis and LC-MS/MS. A significant increase of myogenin expression at day 8 marked the transition from proliferation to differentiation. Of the 898 spots in the proteome analysis, the 25 protein spots overexpressed on day 4 and the 15 protein spots overexpressed on day 8 indicate the end of proliferation and the beginning of differentiation, respectively. Proliferation was characterized by enrichment of proteins involved in actin cytoskeleton remodelling and in cellular metabolic processes (transcription, ubiquitination, response to stress and glucose metabolism). During differentiation, 41 proteins were overexpressed and 51 underexpressed; many of them related to biosynthetic processes (RNA and protein synthesis and folding, and pentose pathways), terminal myotube formation and muscle contraction. The main cellular processes of both phases of muscle development in fish are similar with those observed in mammals but extended in time, allowing sequential studies of myogenesis.

PURPOSE The KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2–positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE. METHODS Patients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery). RESULTS Of patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment. CONCLUSION Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

There is limited evidence on the efficacy and safety of anti-programmed cell death protein 1 (PD-1)-/anti-programmed death-ligand 1 (PD-L1)-based immunotherapy in the elderly, particularly those aged over 75 years. The clinical response and toxicity profile of anti-PD-1-/anti-PD-L1-based immunotherapy in patients aged over 75 years were assessed in this retrospective observational study conducted in the Medical Oncology Service of a tertiary level hospital. The associations among clinical responses, adverse events, and geriatric syndromes were evaluated. In total, 20 patients aged between 75 and 94 years were evaluated. Pembrolizumab and nivolumab were the most commonly used drugs. A clinical benefit (stable disease, partial response or complete response) was documented in 13 patients (65%). This proportion was 80% in patients aged between 75 and 79 years, and 50% in those aged over 79 years (p = 0.236). The adverse events were similar to those reported in younger patients. At least one clinical adverse event (cAE) and one laboratory adverse event (lAE) was reported in 75% and 55% of patients, respectively. Polypharmacy was observed for all patients and multi-morbidity in 95%. Patients without gait disorders showed more responses to immunotherapy. The number of lAEs was significantly associated with the number of commonly prescribed drugs (slope = 0.218, p = 0.010), the Eastern Cooperative Oncology Group score, and the number of cAEs. The elderly can obtain benefits from anti-PD-1-/anti-PD-L1-based immunotherapy. The toxicity profile was similar to that reported in younger counterparts.

The selection of sleeping sites and sleeping trees in nonhuman primates is related to social and ecological factors. We investigate the role of body stability, risk of parasite infection, access to food, and range defense in the sleeping behavior of black-and-gold howler monkeys (Alouatta caraya) in northern Argentina. We collected data for 4 groups over 12 mo (198 study days). Black-and-gold howlers used 12 of 36 available tree species as sleeping trees. In comparison to the available trees, sleeping trees had a larger diameter at breast height, greater total height, and greater height of the lowest branch. Monkeys used large branches to sleep more frequently than small branches. Our results suggest that howlers avoided using the same sleeping tree on consecutive nights. At sleeping trees, individuals descended to lower branches to defecate. Sleeping sites were close to morning feeding sites. More sleeping sites were located in areas of range overlap between groups (75%) than in exclusive-use areas (25%), and sleeping sites located in overlapping areas were used more frequently when neighboring groups were nearby than when they were far away. Our results suggest that body stability, parasite avoidance, access to food, and range defense all affect the selection of sleeping sites. Fil: Brividoro, Melina Victoria. Centro de Investigaciones del Bosque Atlántico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú; Argentina Fil: Kowalewski, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Biológica de Usos Múltiples (Sede Corrientes); Argentina Fil: Scarry, Clara J. California State University; Estados Unidos Fil: Oklander, Luciana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú; Argentina

The PD-L1 inhibitor atezolizumab received US FDA accelerated approval as treatment for PD-L1-positive metastatic triple-negative breast cancer (TNBC). In IMpassion130, combining atezolizumab with first-line nab-paclitaxel for metastatic TNBC significantly improved progression-free survival and showed a clinically meaningful effect on overall survival in patients with PD-L1-positive tumors. The placebo-controlled randomized Phase III IMpassion132 (NCT03371017) trial is evaluating atezolizumab with first-line chemotherapy (capecitabine [mandatory in platinum-pretreated patients] or gemcitabine/carboplatin) for inoperable locally advanced/metastatic TNBC recurring ≤12 months after completing standard (neo)adjuvant anthracycline and taxane chemotherapy. Stratification factors are: visceral metastases, tumor immune cell PD-L1 status and selected chemotherapy. Patients are randomized to atezolizumab 1200 mg or placebo every 3 weeks with the chosen chemotherapy, continued until progression, unacceptable toxicity or withdrawal. The primary end point is overall survival.

GEICAM/2006–10 compared anastrozole (A) versus fulvestrant plus anastrozole (A + F) to test the hypothesis of whether a complete oestrogen blockade is superior to aromatase inhibitors alone in breast cancer patients receiving hormone adjuvant therapy. Multicenter, open label, phase III study. HR+/HER2− EBC postmenopausal patients were randomized 1:1 to adjuvant A (5 years [year]) or A + F (A plus F 250 mg/4 weeks for 3 year followed by 2 year of A). Stratification factors: prior chemotherapy (yes/no); number of positive lymph nodes (0/1–3/≥ 4); HR status (both positive/one positive) and site. Primary objective: disease-free survival (DFS). Planned sample size: 2852 patients. The study has an early stop due to the financer decision with 870 patients (437 randomized to A and 433 to A + F). Patient characteristics were well balanced. After a median follow-up of 6.24y and 111 DFS events (62 in A and 49 in A + F) the Hazard Ratio for DFS (combination vs. anastrozole) was 0.84 (95% CI 0.58–1.22; p = 0.352). The proportion of patients disease-free in arms A and A + F at 5 year and 7 year were 90.8% versus 91% and 83.6% versus 86.7%, respectively. Most relevant G2-4 toxicities (≥ 5% in either arm) with A versus A + F were joint pain (14.7%; 13.7%), fatigue (2.5%; 7.2%), bone pain (3%; 6.5%), hot flushes (3.5%; 5%) and muscle pain (2.8%; 5.1%). The GEICAM/2006–10 study did not show a statistically significant increase in DFS by adding adjuvant F to A, though no firm conclusions can be drawn because of the limited sample size due to the early stop of the trial. ClinicalTrials.gov: NCT00543127.

Herpes simplex virus-type 1 (HSV-1) infection of sensory neurons may lead to a significant reduction in the expression of voltage-activated Na(+) and Ca(2+) channels, which can disrupt the transmission of pain information. Viral infection also results in the secretion of various pro-inflammatory cytokines, including interleukin (IL)-6. In this work, we tested whether IL-6 regulates the expression of Na(+) and Ca(2+) channels post HSV-1 infection in ND7/23 sensory-like neurons. Our results demonstrate that HSV-1 infection causes a significant decrease in the protein expression of the Cav3.2 T-type Ca(2+) channel subunit, despite increasing Cav3.2 mRNA synthesis. Neither Cav3.2 mRNA nor total protein content was affected by IL-6 treatment post HSV-1 infection. In ND7/23 cells, HSV-1 infection caused a significant reduction in the expression of Na(+) and T-type Ca(2+) channels within 48 h. Exposure of ND7/23 cells to IL-6 for 24 h post infection reverses the effect of HSV-1, resulting in a significant increase in T-type Ca(2+) current density. However, Na(+) currents were not restored by 24 h-treatment with IL-6 post HSV-1 infection of ND7/23 cells. The ability of IL-6 to increase the functional expression of T-type Ca(2+) channels on the membrane was blocked by inhibition of protein trafficking with brefeldin-A and ERK1/2 activation. These results indicate that IL-6 release following HSV-1 infection regulates the expression of T-type Ca(2+) channels, which may alter the transmission of pain information.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

The contamination by heavy metals constitutes an environmental problem of great importance in the last decades, and demands of society for clean environments are increasingly evident. To achieve this goal, several strategies have appeared for the in situ remediation of soil contamination caused by heavy metals. This study evaluated two types of iron-based nanoparticles, zero-valent iron nanoparticles (nZVI) and Fe3O4 nanoparticles, for the effective immobilization of Furthermore, we conducted a set of ecotoxicological bioassays: Microtox® Test, Caenorhabditis elegans Test, and Phytoplankton Toxicity Tests, on selected soil and aquatic test organisms to both, i) evaluate the potential ecotoxicological risks associated with nanoparticles treatment, and ii) to define sensitive organisms to be used as suitable bioindicators of heavy metals pollution. The application of 5% nZVI significantly reduced the amount of bioavailable heavy metals, which was effective from an ecotoxicity point of view as a reduction of the toxicity of was observed. Among the bioassays used, C. elegans seems the most effective reference organism in detecting changes in the toxicity of and therefore, C. elegans was found to be a sensitive heavy metals pollution bioindicator. When the Combination index (CI) was obtained to determine combined heavy metals interactions, the results indicated that toxicity would be higher than that expected for Pb, Cd and Zn individually considered, due to the proved antagonistic interactions of those toxicants. The obtained results suggested that nZVI nanoparticles are susceptible to be used as a soil remediation strategy for heavy metal pollution, although a short reactive lifespan must be considered, and therefore its effectiveness in long periods remains to be elucidated.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

Marine land-based Recirculating Aquaculture Systems (RAS) are generally perceived as environmentally friendly aquatic production systems. To promote their sustainability even further and reduce the discharge of nutrients, there is a need for cost-effective end-of-pipe treatment technologies for removing nutrients. This includes nitrate-nitrogen (NO3−-N) for which well-proven technologies for freshwater systems exists, while similar technologies for saltwater systems are less advanced. Granular technology has been developed since the 1970s in wastewater treatment under the upflow anaerobic sludge bed (UASB) concept. This concept is based on the enrichment of different bacterial aggregations into a compact granule, optimizing synergistic and syntrophic bacterial processes by reducing the diffusion distance of substrates between the different bacterial consortia forming the granule. The following study examined the: 1) granular formation; and 2) nitrate removal capacity of a marine Upflow Anoxic Sludge Bed (UASB) reactor operating at different up-flow velocities (0.40–2.11 m/h). The results showed that marine denitrifying granules developed within 27 days using preconditioned rainbow trout (Oncorhynchus mykiss) organic matter waste, and that the highest specific denitrification rate (321.9 ± 13.1 mg NO3−-N/g Total Volatile Suspended Solids (TVSS)/d) was found at an upflow velocity of 0.97 m/h. The marine UASB denitrifying granule reactor had a total capacity of removing 14.9 kg NO3−-N/m3 reactor volume per day at a hydraulic retention time of 1.9 h, making it a strong candidate for end-of-pipe denitrification of marine RAS effluent as well as for in-line treatment in marine systems.