Optimization of Convolutional Neural Network ensemble classifiers by Genetic Algorithms

Breast cancer exhibits a high mortality rate and it is the most invasive cancer in women. An analysis from histopathological images could predict this disease. In this way, computational image processing might support this task. In this work a proposal which employes deep learning convolutional neural networks is presented. Then, an ensemble of networks is considered in order to obtain an enhanced recognition performance of the system by the consensus of the networks of the ensemble. Finally, a genetic algorithm is also considered to choose the networks that belong to the ensemble. The proposal has been tested by carrying out several experiments with a set of benchmark images.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Comparative sensitivity of tumor and non-tumor cell lines as reliable approach for in vitro cytotoxicity screening of lysine-based surfactants with potential pharmaceutical applications

Surfactants are used as additives in topical pharmaceuticals and drug delivery systems. The biocompatibility of amino acid-based surfactants makes them highly suitable for use in these fields, but tests are needed to evaluate their potential toxicity. Here we addressed the sensitivity of tumor (HeLa, MCF-7) and non-tumor (3T3, 3T6, HaCaT, NCTC 2544) cell lines to the toxic effects of lysine-based surfactants by means of two in vitro endpoints (MTT and NRU). This comparative assay may serve as a reliable approach for predictive toxicity screening of chemicals prior to pharmaceutical applications. After 24-h of cell exposure to surfactants, differing toxic responses were observed. NCTC 2544 and 3T6 cell lines were the most sensitive, while both tumor cells and 3T3 fibroblasts were more resistant to the cytotoxic effects of surfactants. IC50-values revealed that cytotoxicity was detected earlier by MTT assay than by NRU assay, regardless of the compound or cell line. The overall results showed that surfactants with organic counterions were less cytotoxic than those with inorganic counterions. Our findings highlight the relevance of the correct choice and combination of cell lines and bioassays in toxicity studies for a safe and reliable screen of chemicals with potential interest in pharmaceutical industry

Mechanisms underlying cytotoxicity induced by engineered nanomaterials: a review of in vitro studies

Engineered nanomaterials are emerging functional materials with technologically interesting properties and a wide range of promising applications, such as drug delivery devices, medical imaging and diagnostics, and various other industrial products. However, concerns have been expressed about the risks of such materials and whether they can cause adverse effects. Studies of the potential hazards of nanomaterials have been widely performed using cell models and a range of in vitro approaches. In the present review, we provide a comprehensive and critical literature overview on current in vitro toxicity test methods that have been applied to determine the mechanisms underlying the cytotoxic effects induced by the nanostructures. The small size, surface charge, hydrophobicity and high adsorption capacity of nanomaterial allow for specific interactions within cell membrane and subcellular organelles, which in turn could lead to cytotoxicity through a range of different mechanisms. Finally, aggregating the given information on the relationships of nanomaterial cytotoxic responses with an understanding of its structure and physicochemical properties may promote the design of biologically safe nanostructures

Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer

Bispecific T cell engagers (BiTEs), a subset of bispecific antibodies (bsAbs), can promote a targeted cancer cell’s death by bringing it close to a cytotoxic T cell. Checkpoint inhibitory T cell engagers (CiTEs) comprise a BiTE core with an added immunomodulatory protein, which serves to reverse cancer-cell immune-dampening strategies, improving efficacy. So far, protein engineering has been the main approach to generate bsAbs and CiTEs, but improved chemical methods for their generation have recently been developed. Homogeneous fragment-based bsAbs constructed from fragment antigen-binding regions (Fabs) can be generated using click chemistry. Here we describe a chemical method to generate biotin-functionalized three-protein conjugates, which include two CiTE molecules, one containing an anti-PD-1 Fab and the other containing an immunomodulatory enzyme, Salmonella typhimurium sialidase. The CiTEs’ efficacy was shown to be superior to that of the simpler BiTE scaffold, with the sialidase-containing CiTE inducing substantially enhanced T cell-mediated cytotoxicity in vitro. The chemical method described here, more generally, enables the generation of multi-protein constructs with further biological applications. [Figure not available: see fulltext.

Nanoparticles incorporating pH-responsive surfactants as a viable approach to improve the intracellular drug delivery

The pH-responsive delivery systems have brought newadvances in the field of functional nanodevices and might allow more accurate and controllable delivery of specific cargoes, which is expected to result in promising applications in different clinical therapies. Here we describe a family of chitosan TPP (tripolyphosphate) nanoparticles (NPs) for intracellular drug delivery, which were designed using two pH-sensitive amino acid-based surfactants fromthe family Nα,Nε-dioctanoyl lysine as bioactive compounds. Lowand mediummolecularweight chitosan (LMW-CS and MMW-CS, respectively) were used for NP preparation, and it was observed that the size distribution for NPs with LMW-CS were smaller (~168 nm) than that for NPs prepared with MMW-CS (~310 nm). Hemolysis assay demonstrated the pH-dependent biomembrane disruptional capability of the constructed NPs. The nanostructures incorporating the surfactants cause negligible membrane permeabilization at pH 7.4. However, at acidic pH, prevailing in endosomes, membrane-destabilizing activity in an erythrocyte lysis assay became evident. When pH decreased to 6.6 and 5.4, hemolytic capability of chitosan NPs increased along with the raise of concentration. Furthermore, studies with cell culture showed that these pH-responsive NPs displayed low cytotoxic effects against 3T3 fibroblasts. The influence of chitosan molecular weight, chitosan to TPP weight ratio, nanoparticle size and nature of the surfactant counterion on the membrane-disruptive properties of nanoparticleswas discussed in detail. Altogether, the results achieved here showed that by inserting the lysine-based amphiphiles into chitosan NPs, pH-sensitive membranolytic and potentially endosomolytic nanocarriers were developed, which, therefore, demonstrated ideal feasibility for intracellular drug delivery

Informal Caregivers’ Health Literacy in Lisbon, Portugal: A Profile for Health Promotion Prioritization

Health literacy (HL) allows people to access, understand and evaluate health information. Informal caregivers' levels of HL may impact long-term care outcomes. 'Informal caregivers' profile in Lisbon county: a health community approach' is a nurse-led research project aiming to assess informal caregivers' health literacy and associated factors in Lisbon county, as well as to foster the development of a local-specific health literacy strategy. A survey to identify a health/social caregiver profile, including questions about HL (HLS-EU-PT), was submitted to a representative sample of carers. Descriptive and bivariate inferential analysis was developed. Informal caregivers' level of HL was mostly sufficient (n = 99, 38%). More than 60% of caregivers have limited HL regarding health promotion. 'Access', 'Appraisal' and 'Use' are the information processing stages with lower mean scores of HL. Carers with low HL levels appear to be older and to have less education, low knowledge of community resources and decreased wellbeing (p < 0.05). A strategy focused on health promotion-related HL through primary care resources can potentially improve caregivers' knowledge, competencies and motivation, as well as health system sustainability. Reported HLS-EU-PT scores deserve special attention. Future work should emphasize the role of HL-associated factors and health outcomes for caregivers and cared-for persons.info:eu-repo/semantics/publishedVersio

Does Reality Overcome the Expected? Survey on Informal Caregivers' Profile: A Nurse-Led Study in Times of COVID-19

The increasing overload of chronic conditions raises challenges for the health system. Informal caregivers have a major role in ensuring the quality of life of the cared-for person, despite the reported lack of working resources which can lead to unmet needs. This article reports on the first part of a nurse-led research project entitled “Informal caregiver’ profiles in Lisbon county: a health community approach.’ We aimed to support decision-making by developing an informal caregiver profile to promote tailored interventions. A survey addressing the dyad was developed and submitted to a convenient, network-based, stratified sample of carers aged 18 years or above. More than thirty community partners supported the identification of caregivers. Data were submitted to univariate descriptive analysis. A profile of the cared-for person and the informal caregiver was uncovered by identifying 639 caregivers, of whom the majority lived with the cared-for person. Only four percent planned the transition to a caregiver role, and no more than 10% had access to support programs. Approximately half of the respondents found that COVID-19 negatively impacted their performance in the caregiver role. Developing a local and tailored strategy with collaboration between healthcare professionals, academics, and community partners is key to ensuring that meaningful support is provided to caregivers.info:eu-repo/semantics/publishedVersio

A qualitative study exploring the patients' perspective from the 'Reserved Therapeutic Space' nursing intervention in acute mental health units

This study aimed to explore the perspective of people who had experienced treatment as patients at acute mental health units, regarding an intervention model to improve therapeutic relationships in the units, which had been previously designed by the nurses. The study participants were people linked to collectives for social activism in mental health. Six focus groups were held. The results were classified into three themes: (a) the meaning of a space to enable the establishment of a therapeutic relationship, (b) the procedures to implement the space, and (c) the difficulties to overcome to establish the space. For the participants, the Reserved Therapeutic Space intervention was perceived as a space where they could share expectations and needs with the nurses, considering it as both valid and useful to improve the therapeutic relationship in acute units. For the participants, the intervention should be structured in three stages: orientation, follow-up, and discharge. The content of the intervention should be proposed by the patients based on their needs and concerns. The barriers identified for carrying out the intervention were the lack of relational competence, the violation of rights, and the lack of accessibility of nurses. The facilitating elements were the availability of nurses, active listening, and empathy. The resulting intervention model includes realities of both groups, providing insights for nurses to initiate a space with patients and improve their therapeutic relationship. This intervention model could be used by managers to test its effectiveness

PEGylated and poloxamer-modified chitosan nanoparticles incorporating a lysine-based surfactant for pH-triggered doxorubicin release

The growing demand for efficient chemotherapy in many cancers requires novel approaches in target-delivery technologies. Nanomaterials with pH-responsive behavior appear to have potential ability to selectively release the encapsulated molecules by sensing the acidic tumor microenvironment or the low pH found in endosomes. Likewise, polyethylene glycol (PEG)- and poloxamer-modified nanocarriers have been gaining attention regarding their potential to improve the effectiveness of cancer therapy. In this context, DOX-loaded pH-responsive nanoparticles (NPs) modified with PEG or poloxamer were prepared and the effects of these modifiers were evaluated on the overall characteristics of these nanostructures. Chitosan and tripolyphosphate were selected to form NPs by the interaction of oppositely charged compounds. A pH-sensitive lysine-based amphiphile (77KS) was used as a bioactive adjuvant. The strong dependence of 77KS ionization with pH makes this compound an interesting candidate to be used for the design of pH-sensitive devices. The physicochemical characterization of all NPs has been performed, and it was shown that the presence of 77KS clearly promotes a pH-triggered DOX release. Accelerated and continuous release patterns of DOX from CS-NPs under acidic conditions were observed regardless of the presence of PEG or poloxamer. Moreover, photodegradation studies have indicated that the lyophilization of NPs improved DOX stability under UVA radiation. Finally, cytotoxicity experiments have shown the ability of DOX-loaded CS-NPs to kill HeLa tumor cells. Hence, the overall results suggest that these pH-responsive CS-NPs are highly potent delivery systems to target tumor and intracellular environments, rendering them promising DOX carrier systems for cancer therapy