Effectively utilizing publicly available databases for cancer target evaluation.

The majority of compounds designed against cancer drug targets do not progress to become approved drugs, mainly due to lack of efficacy and/or unmanageable toxicity. Robust target evaluation is therefore required before progressing through the drug discovery process to reduce the high attrition rate. There are a wealth of publicly available databases that can be mined to generate data as part of a target evaluation. It can, however, be challenging to learn what databases are available, how and when they should be used, and to understand the associated limitations. Here, we have compiled and present key, freely accessible and easy-to-use databases that house informative datasets from in vitro, in vivo and clinical studies. We also highlight comprehensive target review databases that aim to bring together information from multiple sources into one-stop portals. In the post-genomics era, a key objective is to exploit the extensive cell, animal and patient characterization datasets in order to deliver precision medicine on a patient-specific basis. Effective utilization of the highlighted databases will go some way towards supporting the cancer research community achieve these aims.

Optimization of Natural Antioxidants Extraction from Pineapple Peel and Their Stabilization by Spray Drying.

Pineapple peel still contains an important amount of phenolic compounds and vitamins with valuable antioxidant activity. In this way, the aim of this study was the recovery of the bioactive compounds from pineapple peel using environmentally friendly and low-cost techniques, envisaging their application in food products. From the solid-liquid extraction conditions tested, the one delivering an extract with higher total phenolic content and antioxidant capacity was a single extraction step with a solvent-pineapple peel ratio of 1:1 (w/w) for 25 min at ambient temperature, using ethanol-water (80-20%) as a solvent. The resulting extract revealed a total phenolic content value of 11.10 ± 0.01 mg gallic acid equivalent (GAE)/g dry extract, antioxidant activity of 91.79 ± 1.98 µmol Trolox/g dry extract by the DPPH method, and 174.50 ± 9.98 µmol Trolox/g dry extract by the FRAP method. The antioxidant rich extract was subjected to stabilization by the spray drying process at 150 °C of inlet air temperature using maltodextrin (5% w/w) as an encapsulating agent. The results showed that the antioxidant capacity of the encapsulated compounds was maintained after encapsulation. The loaded microparticles obtained, which consist of a bioactive powder, present a great potential to be incorporated in food products or to produce bioactive packaging systems.

Urgent/emergency surgery during COVID-19 state of emergency in Portugal: a retrospective and observational study.

Background: SARS-CoV-2 virus changed society's behaviour. Population was advised to reduce unnecessary heath care use to accommodate urgent cases and daily increase of COVID-19 patients. Health care facilities faced huge challenges, having to readjust their response to preserve good quality of care. In Portugal, a significant reduction in the number of admissions to the Emergency Department (ED) was reported all over the country, however the impact on the dynamics of undeferrable surgery remains to be reported. This study compares the volume and characteristics of urgent/emergency surgery during the 2020 COVID-19 pandemic with the homologous period in 2019, chronologically illustrating the national evolution of new COVID-19 cases and the social and hospital containment response. Methods: A retrospective observational study was conducted in a tertiary hospital center located in the most affected region by COVID-19 in Portugal. Medical records of patients who underwent urgent/emergency surgery between March 1st and May 2nd of both 2020 and 2019 were examined and the volume of surgeries were compared. Also, daily national updates from Portuguese Directorate-General for Health were analysed. Results: During the COVID-19 pandemic approximately 30% less patients underwent urgent/emergency surgery (99%CI = 0.18-0.61, p < 0.001). Waiting time for surgery showed no difference between both years (p = 0.068), but patients who did surgery during the 2020 pandemic had higher mortality rates than the ones who did it in 2019 (11.4% in 2020 and 5.9% in 2019, p = 0.001). Reduction in surgery volume was correlated with the increasing number of infected cases nationally. Conclusion: This study demonstrates decreasing numbers of urgent/emergency procedures during the COVID-19 pandemic that may be justified by the national growth number of infected cases. Preoperative mass screening strategy was implemented without compromising the efficiency of surgical service, but patients' mortality was higher. The importance of visiting the ED during COVID-19 pandemic for serious cases that cannot be managed in other settings should be highlighted.

Application of Edible Alginate Films with Pineapple Peel Active Compounds on Beef Meat Preservation.

Alginate-based edible films containing natural antioxidants from pineapple peel were applied in the microbial spoilage control, color preservation, and barrier to lipid oxidation of beef steaks under storage at 4 °C for five days. Different stabilization methods of pineapple peel compounds were used before incorporation into alginate films, including extracted compounds with an hydroalcoholic solvent encapsulated in microparticles, microparticles produced by spray-drying pineapple peel juice, and particles obtained by milling freeze dried pineapple peel. Bioactive films exhibited higher antioxidant activity (between 0.15 µmol to 0.35 µmol FeSO4.7H2O/g dried film) than the alginate film without these compounds (0.02 µmol FeSO4.7H2O/g dried film). Results showed that control films without active compounds had no significant effect on decreasing the microbial load of aerobic mesophilic and Pseudomonas spp., while the films containing encapsulated hydroalcoholic extract showed a significant inhibitory effect on microbial growth of meat at two days of storage. Alginate films containing peel encapsulated extract were effective for maintaining the color hue and intensity of red beef meat samples. Pineapple peel antioxidants have the potential to retard lipid oxidation in meat samples, and the possibility of incorporation of a higher amount of pineapple peel bioactive compounds in the films should be investigated.

Microencapsulation of Pineapple Peel Extract by Spray Drying Using Maltodextrin, Inulin, and Arabic Gum as Wall Matrices.

A pineapple peel hydroalcoholic extract rich in phenolic compounds, was stabilized by microencapsulation using spray drying technology, with maltodextrin, inulin, and arabic gum as wall materials. The influence of the type of wall material and drying temperature (150 and 190 °C) on the particles properties was studied. The particles presented a spherical shape with a diameter ranging from approximately 1.3 to 18.2 µm, the exception being the ones with inulin that showed a large degree of agglomeration. All powders produced presented an intermediate cohesiveness and a fair to good flowability according to Carr index and Hausner ratio, which envisages suitable handling properties at an industrial scale. The microencapsulation processes using maltodextrin and arabic gum at 150 °C were the ones that showed higher maintenance of the antioxidant activity of compounds present in the extract before encapsulation during spray drying. In addition, the microparticles obtained were quite efficient in stabilizing the encapsulated phenolic compounds, as their antioxidant activity did not change significantly during six months of storage at 5 °C.

Antioxidants of Natural Plant Origins: From Sources to Food Industry Applications.

In recent years, great interest has been focused on using natural antioxidants in food products, due to studies indicating possible adverse effects that may be related to the consumption of synthetic antioxidants. A variety of plant materials are known to be natural sources of antioxidants, such as herbs, spices, seeds, fruits and vegetables. The interest in these natural components is not only due to their biological value, but also to their economic impact, as most of them may be extracted from food by-products and under-exploited plant species. This article provides an overview of current knowledge on natural antioxidants: their sources, extraction methods and stabilization processes. In addition, recent studies on their applications in the food industry are also addressed; namely, as preservatives in different food products and in active films for packaging purposes and edible coatings.

Avoidable cancers in the Nordic countries-the potential impact of increased physical activity on postmenopausal breast, colon and endometrial cancer.

BACKGROUND: Physical activity has been shown to reduce the risk of colon, endometrial and postmenopausal breast cancer. The aim of this study was to quantify the proportion of the cancer burden in the Nordic countries linked to insufficient levels of leisure time physical activity and estimate the potential for cancer prevention for these three sites by increasing physical activity levels. METHODS: Using the Prevent macrosimulation model, the number of cancer cases in the Nordic countries over a 30-year period (2016-2045) was modelled, under different scenarios of increasing physical activity levels in the population, and compared with the projected number of cases if constant physical activity prevailed. Physical activity (moderate and vigorous) was categorised according to metabolic equivalents (MET) hours in groups with sufficient physical activity (15+ MET-hours/week), low deficit (9 to <15 MET-hours/week), medium deficit (3 to <9 MET-hours/week) and high deficit (<3 MET-hours/week). RESULTS: If no one had insufficient levels of physical activity, about 11,000 colon, endometrial and postmenopausal breast cancer cases could be avoided in the Nordic countries in a 30-year period, which is 1% of the expected cases for the three cancer types. With a 50% reduction in all deficit groups by 2025 or a 100% reduction in the group of high deficit, approximately 0.5% of the expected cases for the three cancer types could be avoided. The number and percentage of avoidable cases was highest for colon cancer. CONCLUSION: 11,000 cancer cases could be avoided in the Nordic countries in a 30-year period, if deficit in physical activity was eliminated.

Avoidable colorectal cancer cases in Denmark - The impact of red and processed meat.

BACKGROUND: High red and processed meat intakes are associated with increased colorectal cancer (CRC) risk. The effect of eliminating or reducing red and processed meat consumption on CRC burden was not previously quantified in Denmark. The aim of this study was to calculate the possible effects of reductions in red and processed meat consumption on future CRC incidence in the Danish adult population. METHODS: Under six scenarios of prevalence exposure (meat consumption) the number of CRC cases in Denmark for a 30-year period (2016-2045) was estimated and compared to the projected number of CRCs if the prevalence of meat consumption remains constant. Data was obtained from the NORDCAN register, Statistics Denmark, and from the Danish dietary survey data (DANSDA). Analyses were conducted using the Prevent model. RESULTS: During the 30-year period, a total of 36,767 (19.8%) CRC cases out of 185,937 expected could be avoided in Denmark by eliminating the consumption of both red and processed meat. For the same period, a modest reduction in both red and processed meat consumption could lead to the prevention of 16,964 (9.1%) CRC cases. The greatest reductions were seen among men, and the highest impact was estimated for the elimination or reduction of processed meat consumption. CONCLUSION: Decreased red and processed meat consumption could reduce the burden of CRC markedly in Denmark. These results can assist public health planners and help highlight the important role of a modest but realistic reduction in meat consumption in the prevention of CRC.

Using a bacterial fucose-rich polysaccharide as encapsulation material of bioactive compounds.

The potential of a bacterial exopolysaccharide named FucoPol, produced by the bacterium Enterobacter A47, as encapsulation matrix was explored. Spherical capsules with a smooth surface were produced by spray drying. The obtained microcapsules had average diameters ranging from 0.5 to 26.7µm and presented thin walls (thickness from 222 to 1094nm). The capsules were loaded with two bioactive compounds: gallic acid (GA) and oregano essential oil (OEO). Both bioactive materials were encapsulated in FucoPol particles, retaining their antioxidant activity after the drying process. Release studies showed that GA release in simulated gastric and intestinal fluids was faster than that of OEO, envisaging that the latter had established stronger interactions with the polymer matrix. These results suggest that FucoPol has a good potential for use as encapsulating material of bioactive compounds for application in several areas, including food, cosmetic or pharmaceutical products.

Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are being extensively researched for cell therapy and tissue engineering. We have engineered MSCs to express the pro-apoptotic protein tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and are currently preparing this genetically modified cell therapy for a phase 1/2a clinical trial in patients with metastatic lung cancer. To do this, we need to prepare a cryopreserved allogeneic MSCTRAIL cell bank for further expansion before patient delivery. The effects of cryopreservation on a genetically modified cell therapy product have not been clearly determined. METHODS: We tested different concentrations of dimethyl sulfoxide (DMSO) added to the human serum albumin ZENALB 4.5 and measured post-thaw cell viability, proliferation ability and differentiation characteristics. In addition, we examined the homing ability, TRAIL expression and cancer cell-killing capacities of cryopreserved genetically modified MSCs compared with fresh, continually cultured cells. RESULTS: We demonstrated that the post-thaw viability of MSCs in 5% DMSO (v/v) with 95% ZENALB 4.5 (v/v) is 85.7 ± 0.4%, which is comparable to that in conventional freezing media. We show that cryopreservation does not affect the long-term expression of TRAIL and that cryopreserved TRAIL-expressing MSCs exhibit similar levels of homing and, importantly, retain their potency in triggering cancer cell death. CONCLUSIONS: This study shows that cryopreservation is unlikely to affect the therapeutic properties of MSCTRAIL and supports the generation of a cryopreserved master cell bank.

CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

Although squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix account for up to 30% of cancer deaths, the mechanisms that regulate disease progression remain incompletely understood. Here, we use gene transduction and human tumor xenograft assays to establish that the tumour suppressor Cell adhesion molecule 1 (CADM1) inhibits SqCC proliferation and invasion, processes fundamental to disease progression. We determine that the extracellular domain of CADM1 mediates these effects by forming a complex with HER2 and integrin α6ß4 at the cell surface that disrupts downstream STAT3 activity. We subsequently show that treating CADM1 null tumours with the JAK/STAT inhibitor ruxolitinib mimics CADM1 gene restoration in preventing SqCC growth and metastases. Overall, this study identifies a novel mechanism by which CADM1 prevents SqCC progression and suggests that screening tumours for loss of CADM1 expression will help identify those patients most likely to benefit from JAK/STAT targeted chemotherapies.

Menu labelling is effective in reducing energy ordered and consumed: a systematic review and meta-analysis of recent studies.

OBJECTIVE: Menu labelling is a practical tool to inform consumers of the energy content of menu items and help consumers make informed decisions in the eating-out environment, and the volume of studies published recently regarding its effects is expanding, both quantitatively and geographically. The aim of the present review and meta-analysis is to consider the most recent evidence which assesses the effect of menu labelling regarding changes in energy consumed, ordered or selected in both real-world and experimental settings. DESIGN: The review included fifteen peer-reviewed, full-text articles published between 2012 and 2014. Pertinent methodological information was extracted from each of the included studies and a quality assessment scheme was applied to classify the studies, after which systematic across-study comparisons were conducted. A meta-analysis was conducted including twelve of the fifteen studies, and stratified according to type of research setting and outcome: energy consumed, ordered or selected. RESULTS: The rating yielded studies categorized by study quality: good (n 3), fair (n 9) and weak (n 3). Overall nine studies showed statistically significant reductions in energy consumed, ordered or selected. Three articles reported no effect of menu labelling. The meta-analysis showed statistically significant effects of menu labelling: overall energy consumed was reduced by a mean of 419·5 kJ (100·2 kcal) and energy ordered in real-world settings decreased by a mean of 325·7 kJ (77·8 kcal). CONCLUSIONS: The review supports that menu labelling can effectively reduce energy ordered and consumed in the away-from-home food environment.

Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors.

Mesenchymal stromal cells (MSCs) are inherently tumor homing and can be isolated, expanded, and transduced, making them viable candidates for cell therapy. This tumor tropism has been used to deliver anticancer therapies to various tumor models. In this study, we sought to discover which molecules are the key effectors of human MSC tumor homing in vitro and using an in vivo murine model. In this study, we discover a novel role for macrophage migration inhibitory factor (MIF) as the key director of MSC migration and infiltration toward tumor cells. We have shown this major role for MIF using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Additionally, we demonstrate physical interaction between MIF and three receptors: CXCR2, CXCR4, and CD74. CXCR4 is the dominant receptor used by MIF in the homing tumor context, although some signaling is observed through CXCR2. We demonstrate downstream activation of the MAPK pathway necessary for tumor homing. Importantly, we show that knockdown of either CXCR4 or MIF abrogates MSC homing to tumors in an in vivo pulmonary metastasis model, confirming the in vitro two-dimensional and three-dimensional assays. This improved understanding of MSC tumor tropism will further enable development of novel cellular therapies for cancers.

Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma.

Malignant pleural mesothelioma is a rare but devastating cancer of the pleural lining with no effective treatment. The tumour is often diffusely spread throughout the chest cavity, making surgical resection difficult, while systemic chemotherapy offers limited benefit. Bone marrow-derived mesenchymal stem cells (MSCs) home to and incorporate into tumour stroma, making them good candidates to deliver anticancer therapies. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic molecule that selectively induces apoptosis in cancer cells, leaving healthy cells unaffected. We hypothesised that human MSCs expressing TRAIL (MSCTRAIL) would home to an in vivo model of malignant pleural mesothelioma and reduce tumour growth. Human MSCs transduced with a lentiviral vector encoding TRAIL were shown in vitro to kill multiple malignant mesothelioma cell lines as predicted by sensitivity to recombinant TRAIL (rTRAIL). In vivo MSC homing was delineated using dual fluorescence and bioluminescent imaging, and we observed that higher levels of MSC engraftment occur after intravenous delivery compared with intrapleural delivery of MSCs. Finally, we show that intravenous delivery of MSCTRAIL results in a reduction in malignant pleural mesothelioma tumour growth in vivo via an increase in tumour cell apoptosis.

Role of Oxidized Protein Repair in Human Skeletal Muscle.

There is now increasing evidence that reactive oxygen species (ROS) are signalling molecules that regulate growth, differentiation, proliferation and apoptosis, at least in physiological concentration. However, when ROS levels overcome the capacity of cellular antioxidant systems, they damage cellular components such as nucleic acids, lipids and in particular proteins, inflicting alterations to cell structure and function. Oxidation of sulfur-containing aminoacids, like cysteine and methionine, within proteins, can be repaired by specific enzymatic systems. Indeed methionine sulfoxide is catalytically reduced back to methionine by the methionine sulfoxide reductase (Msr) system. We showed that this Msr system is involved in cellular protection against oxidative stress by preventing apoptosis and limiting irreversible protein oxidative damage. Furthermore, it has been demonstrated that the Msr system is no longer efficient during ageing and senescence as well as that Msr modulates longevity in animal models. In this work we analysed Msr expression in human skeletal muscle. We showed, using both primary and immortalized skeletal muscle cell lines, that the expression of the Msr system increases during differentiation, suggesting a role of this antioxidant system on myofibres formation. Since myoblasts senescence associated with less differentiation capacity and an abnormal production of ROS have been observed in some muscular dystrophies, we wondered about the state of the Msr system in late-onset myopathies, such as oculopharyngeal muscular dystrophy (OPMD). In OPMD we confirmed, at the transcription level, an increased expression of Msr with differentiation, both on immortalized and primary cell cultures, similarly to what we observed on control cell lines. Our aim is to characterize for the first time the role of a major oxidized protein repair system (Msr) in human skeletal muscle homeostasis and, in particular, in myotubes protection during oxidative stress conditions.

O álcool entre nós:impacto do consumo de álcool no casal / El alcohol entre nosotros: impacto del consumo de alcohol en la pareja / "Alcohol among us": The impact of alcohol consumption in the couple

À medida que aumenta o consumo de álcool, as consequências negativas também aumentam na vida do consumidor, e em particular, no capítulo das suas relações interpessoais. Este estudo teve como objectivo reunir a literatura que tem vindo a debruçar-se sobre a influência do álcool na vida conjugal dos consumidores. Ao longo do artigo apresenta-se também uma sumarização dos resultados divulgados em domínios subjacentes como a satisfação marital, a comunicação e a sexualidade.

A medida que aumenta el consumo de alcohol, los efectos negativos también aumentan en la vida del bebedor, en particular, en el capítulo de sus relaciones interpersonales. Este trabajo tuvo como objetivo revisar las publicaciones que se han enfocado en los efectos del alcohol en la relación conyugal. A lo largo del artículo se presenta un resumen de los resultados divulgados en las áreas de la satisfacción marital, la comunicación y la sexualidad de la pareja.

As alcohol consumption increases, the negative effects also increase in the drinker's life, in particular way, in the chapter of their interpersonal relationships. This article meets the literature that focus on the influence of alcohol on the couple relationship. Throughout the article also presents a summary of the results disclosed in couple areas such as marital satisfaction, communication, conflictuality and sexuality.

In vitro reconstitution of Bluetongue virus infectious cores.

Bluetongue virus (BTV) is a vector-borne, nonenveloped icosahedral particle that is organized in two capsids, an outer capsid of two proteins, VP2 and VP5, and an inner capsid (or core) composed of two major proteins, VP7 and VP3, in two layers. The VP3 layer (subcore) encloses viral transcription complex (VP1 polymerase, VP4 capping enzyme, VP6 helicase) and a 10-segmented double-stranded (dsRNA) genome. Although much is known about the BTV capsids, the order of the core assembly and the mechanism of genome packaging remain unclear. Here, we established a cell-free system to reconstitute subcore and core structures with the proteins and ssRNAs, demonstrating that reconstituted cores are infectious in insect cells. Furthermore, we showed that the BTV ssRNAs are essential to drive the assembly reaction and that there is a distinct order of internal protein recruitment during the assembly process. The in vitro engineering of infectious BTV cores is unique for any member of the Reoviridae and will facilitate future studies of RNA-protein interactions during BTV core assembly.

Aortic and tricuspid endocarditis due to Streptococcus gallolyticus in an immunocompetent patient with a normal heart.

Endocarditis due to Streptococcus gallolyticus, an agent previously included in the Streptococcus bovis denomination is a serious disease, often associated with lesions of the colon mucosa. Aortic valve is more often affected and tricuspid involvement is quite rare. We present a case of a 56-year-old man who was admitted with a 2-month history of fever. Echocardiogram revealed vegetations on the aortic and tricuspid valve and blood cultures grew S. gallolyticus. Thoracic X-ray and computed tomography were consistent with septic pulmonary embolism. Despite optimal antibiotic therapy he developed an ischemic stroke and acute aortic regurgitation, which led to emergent surgery. Colonoscopy found a benign adenoma which was excised, and the patient had a full recovery.

Blood loss anemia due to adenocarcinoma of the jejunum: case report and review of the literature.

BACKGROUND: Small bowel tumors are rare, accounting for only 3-6% of gastrointestinal neoplasms, 1-2% of these being malignant. They must be considered whenever a patient presents with gastrointestinal bleeding, with normal upper gastrointestinal endoscopy and colonoscopy. CASE PRESENTATION: We report a case of jejunal adenocarcinoma presenting as a blood loss anemia in a 65 year-old male, doing a brief review on the subject. CONCLUSION: Our case intends to highlight the fact that small bowel tumours are rare and frequently present to the Internist as non-specific clinical symptoms.

A cell-based bicistronic lentiviral reporter system for identification of inhibitors of the hepatitis C virus internal ribosome entry site.

This report describes the development, optimization and implementation of a persistent cell-based system to test inhibitors of hepatitis C (HCV) translation. The assay is based on a heterologous human immunodeficiency virus-1/simian immunodeficiency virus (HIV-1/SIV) lentiviral vector expressing the bicistronic cassette containing the firefly and renilla luciferase genes, respectively, as reporters, and the HCV internal ribosome entry site (IRES) inserted in between, under the control of the cytomegalovirus (CMV) promoter. The drug target in this assay is the HCV IRES, the activity of which leads to modulation of the renilla luciferase gene expression under its control, which is monitored by luminometry. The system has been validated using interferon (IFN), which is still the only consensual antiviral agent against HCV infection, associated with ribavirin. This bicistronic vector, extended to other viral IRESs and assayed in different cell lines, exhibited weak cell tropism, allowing its broad use in gene therapy, which frequently needs a multicistronic transfer vector to follow the expression of a gene of interest inside the target cells with the aid of a reporter, a drug selection marker, or a suicide gene, expressed from the same transcript.