IMMUNEPOTENT CRP enhances cyclophosphamide-induced cytotoxicity through a caspase independent but ROS dependent mechanism in triple negative-breast cancer cells

Background: Breast cancer (BC) is one of the leading causes of cancer death worldwide. Cyclophosphamide (CYP) remains a mainstay in cancer therapy mainly in the triple negative breast cancer subtype (TNBC) in spite of harmful adverse effects and cell death-resistances. To face this, combination of chemotherapies and immunotherapies has been proposed. IMMUNEPOTENT CRP (ICRP) is an immunotherapy that has cytotoxic effects in several cancer cells without affecting peripheral blood mononuclear cells (PBMC) and CD3+ cells, beside improving clinical parameters of chemotherapy-treated patients. The aim of this study was to evaluate the mechanism of cytotoxicity induced by ICRP in combination with CYP (ICRP+CYP) in TNBC cells and their effect in healthy cells. Methods: For this purpose, human and murine breast adenocarcinoma, MDA-MB-231 and 4T1 cells, beside PBMC were treated for 24 hours with ICRP, CYP or ICRP+CYP in different combination ratios for the assessment of cell death. Flow cytometry was used to determine biochemical characteristics of cell death. Results: ANN/PI assays showed that ICRP+CYP induce cell cycle arrest in TNBC cells and potentiated cell death characterized by loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and caspases activation. In addition, ICRP+CYP-cell death is ROS-dependent and caspases-independent in MDA-MB-231 and 4T1 cells. On the other hand, ICRP did not affect CYP-cytotoxicity in PBMC. Conclusions: For all the above, we can propose that the combination of ICRP with CYP is an effective combination therapy, promoting their use even in tumoral cells with defects on proteins implicated in the apoptotic pathway

Response of obesity-resistant BALB/c mice to a ketogenic diet

Introduction. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet in which the body undergoes metabolic adjustments that stimulate ketogenesis, thereby increasing circulating ketone bodies. Loss of body weight is attributed to these adjustments, as well as neuroprotective properties. However, the mechanisms involved are still not fully elucidated. That aim of this work was to evaluate the effect of a ketogenic diet on body composition, feeding behavior and glucose metabolism in mice of the BALB/c strain, a mouse model resistant to obesity. Materials and methods. BALB/c mice of both sexes, 12 weeks old, were divided into KD and control groups, which received a ketogenic diet (Research Diets) or standard chow (LabDiet 5001), respectively, for 23 days. Throughout the experiment, body weight gain, water and food intake were measured, whereas body mass index (BMI), the percentage of interscapular, inguinal, and visceral adipose tissue and blood b-hidroxybutyrate levels were measured at the end of the protocol. In addition, glucose tolerance tests were carried out at the beginning and at the end of the experiment. Results. Similar body weight gain (10%) was observed in males and females on KD compared to the control group (p\u3c0.05). However, a higher BMI was observed only in males. The KD group consumed 50% less food in both sexes, whereas water consumption was diminished 25% in males and 50% in females, compared to the control (p= 0.0001). The estimated energy intake was lower (12 Kcal) in males on ketogenic diet, but not in females. Regarding the metabolic state at day 23, in KD mice levels of b-hidroxybutyrate increased to 0.4 mmol/L in males and 0.7 mmol/L in females. Mice of both sexes on KD showed increased inguinal and visceral fat, when compared to the control group on standard chow. At day 23, the glucose tolerance test showed an increase in the area under the curve, indicating impaired glucose tolerance, in both males and females on KD. Conclusions. In obesity-resistant BALB/c mice, the consumption of a ketogenic diet for a short period induces a state of nutritional ketosis accompanied by weight gain, increased fat tissue, and impaired glucose intolerance

Protease inhibitor monotherapy is associated with a higher level of monocyte activation, bacterial translocation and inflammation

Introduction Monotherapy with protease-inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation. Methods We performed a cross-sectional study comparing patients on successful MPI (n=40) with patients on cART (n=20). Activation, senescence, exhaustion and differentiation stage in CD4+ and CD8+ T lymphocyte subsets, markers of monocyte activation, microbial translocation, inflammation, coagulation and low-level viremia were assessed. Results CD4+ or CD8+ T lymphocyte subset parameters were not significantly different between both groups. Conversely, as compared with triple cART, MPI patients showed a higher proportion of activated monocytes (CD14+ CD16−CD163+ cells, p=0.031), soluble markers of monocyte activation (sCD14 p=0.004, sCD163 p=0.002), microbial translocation (lipopolysaccharide (LPS)-binding protein; LBP p=0.07), inflammation (IL-6 p=0.04) and low-level viremia (p=0.035). In a multivariate model, a higher level of CD14+ CD16−CD163+ cells and sCD14, and presence of very low-level viremia were independently associated with MPI. Monocyte activation was independently associated with markers of inflammation (IL-6, p=0.006), microbial translocation (LBP, p=0.01) and low-level viremia (p=0.01). Conclusions Patients on MPI showed a higher level of monocyte activation than patients on standard therapy. Microbial translocation and low-level viremia were associated with the high level of monocyte activation observed in patients on MPI. The long-term clinical consequences of these findings should be assessed

Contamination level and spatial distribution of heavy metals in water and sediments of El Guájaro Reservoir, Colombia

Heavy metals have become a subject of special concern worldwide, mainly due to high persistence in the environment, toxicity, biogeochemical recycling and ecological risk. Therefore, the objective of this investigation was to analyze the spatial–temporal distribution of heavy metals in water and sediments to determine the environmental status of El Guájaro Reservoir, where such studies have not been developed. Two measurement campaigns (dry and wet period) were carried out and eight sampling stations were selected. A comparison of water and sediment quality parameters with existing national and international regulations was done. Also, heavy metal distribution maps were generated, and the geoaccumulation index was calculated to identify sources and sediments contamination level. Based on the obtained results, agriculture and mining activities are the main causes of the reservoir contamination. This metals levels could be a potential risk for the aquatic life and the populations that are supplied from this water body

The registry of home artificial nutrition and ambulatory of the Spanish society of parenteral and enteral nutrition: Swot analysis

Objetivo: Evidenciar mediante un análisis DAFO-R realizado por consenso de expertos las características más acuciantes del registro de Nutrición Artificial Domiciliaria y Ambulatoria. Material y método: Análisis DAFO-R por consenso de expertos. Se solicitó la participación de los miembros del grupo NADYA activos en los últimos 5 años bajo la premisa de estructurar el DAFO-R sobre las características del registro NADYA desde su inicio. Resultados: Han participado 18 expertos de diferentes hospitales de la geografía española. El análisis interno se inclina positivamente presentando al registro con recursos importantes. En el análisis externo no son numerosas las amenazas, hay factores de gran potencia, “la voluntariedad del registro” y la “dependencia externa de financiación”. Las oportunidades identificadas son importantes. Las recomendaciones se dirigen a la estabilización del sistema disminuyendo las amenazas como foco principal de las estrategias a desarrollar al mismo tiempo que se debe potenciar los puntos identificados en oportunidades y fortalezas. Conclusiones: El registro NADYA se muestra en el análisis con gran potencialidad de mejora. Las recomendaciones propuestas deberán estructurarse para continuar la tendencia de desarrollo y perfeccionamiento de la calidad que ha caracterizado al registro NADYA desde su inicio.Objective: To evidence by means of a SWOT-R analysis performed by an expert consensus the most worrying characteristics of the register on Home-based and Outpatient Artificial Nutrition. Material and methods: SWOT-R analysis with expert consensus. We requested the participation of the active members of the NADYA group within the last 5 years with the premise of structuring the SWOT-R based on the characteristics of the NADYA registry from its beginning. Results: 18 experts from hospitals all over Spain have participated. The internal analysis seems to be positive, presenting the registry as having important resources. The external analysis did not show a great number of threats, there are very potent factors, “the voluntariness” of the registry and the “dependence on external financing”. The opportunities identified are important. The recommendations are aimed at stabilizing the system by decreasing the threats as one of the main focus of the strategies to develop as well as promoting the items identified as opportunities and strengths. Conclusions: The analysis shows that the NADYA register shows a big potentiality for improvement. The proposed recommendations should be structured in order to stay on the track of development and quality improvement that has characterized the NADYA register from the beginnin

The effect of an online exercise programme on bone health in paediatric cancer survivors (iBoneFIT): study protocol of a multi-centre randomized controlled trial

Background: New approaches on paediatric cancer treatment aim to maintain long-term health. As a result of radiotherapy, chemotherapy or surgery, paediatric cancer survivors tend to suffer from any chronic health condition. Endocrine dysfunction represents one of the most common issues and affects bone health. Exercise is key for bone mass accrual during growth, specifically plyometric jump training. The iBoneFIT study will investigate the effect of a 9-month online exercise programme on bone health in paediatric cancer survivors. This study will also examine the effect of the intervention on body composition, physical fitness, physical activity, calcium intake, vitamin D, blood samples quality of life and mental health. Methods: A minimum of 116 participants aged 6 to 18 years will be randomized into an intervention (n = 58) or control group (n = 58). The intervention group will receive an online exercise programme and diet counselling on calcium and vitamin D. In addition, five behaviour change techniques and a gamification design will be implemented in order to increase the interest of this non-game programme. The control group will only receive diet counselling. Participants will be assessed on 3 occasions: 1) at baseline; 2) after the 9 months of the intervention; 3) 4 months following the intervention. The primary outcome will be determined by dual energy X-ray absorptiometry (DXA) and the hip structural analysis, trabecular bone score and 3D-DXA softwares. Secondary outcomes will include anthropometry, body composition, physical fitness, physical activity, calcium and vitamin D intake, blood samples, quality of life and mental health. Discussion: Whether a simple, feasible and short in duration exercise programme can improve bone health has not been examined in paediatric cancer survivors. This article describes the design, rationale and methods of a study intended to test the effect of a rigorous online exercise programme on bone health in paediatric cancer survivors. If successful, the iBoneFIT study will contribute to decrease chronic health conditions in this population and will have a positive impact in the society.The iBoneFIT project is funded by a fellowship from 'la Caixa' Foundation (ID 100010434). The fellowship code is LCF/BQ/PR19/11700007. This study has been partially supported by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Background VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1 x10(13) viral particles (vp)/patient (Part I), and 3.3x10(12) vp/patient (Part II). Fourteen patients were included in Part Ill: there were no DLTs and the RP2D was 1 x10(13) vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1x10(13) vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1 x10(13) vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon- r,soluble lymphocyte activation ne-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paditaxel plus gemcitabine to patients with pancreatic adenocarcinoma