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Introduction: In patients with non-aneurysmal perimesencephalic hemorrhage, spontaneous rebleeding does not occur. The lack of reported recurrences may lead to less cautious administration of antithrombotic therapy.Methods: Case report.Results: A 57-year-old woman with a perimesencephalic pattern of hemorrhage and negative CT angiography was treated with carbasalate calcium and intravenous heparin because of an acute coronary syndrome. Three days after installment of this antithrombotic therapy she experienced a recurrent perimesencephalic hemorrhage leading to hydrocephalus and a decrease in consciousness. She died the same day as a result of ventricular fibrillation.Conclusion: In the early phase after perimesencephalic hemorrhage, anticoagulant therapy may lead to rebleeding. The risks and benefits of antithrombotic therapy should be carefully weighed in patients with a perimesencephalic pattern of hemorrhage and negative CT angiography. [ABSTRACT FROM AUTHOR]

The use of pesticides, such as glyphosate, has increased due to population growth and the rising demand for food. Plant growth-promoting rhizobacteria (PGPR), such as Streptomyces, offer a more ecologically friendly alternative to the excessive use of pesticides. However, these bacteria undergo a complex life cycle involving the formation of hyphae, mycelia, and spores, which makes standardizing laboratory cultures challenging. In this context, we tested three methods for cultivating a Streptomyces isolate (CLV322) in the presence of the stressor agent glyphosate, denoted as M1, M2, and M3. These methods involved the simultaneous addition of the herbicide 24-48 h after the start of cultivation. We evaluated the growth and cell viability of CLV322 using the 2,3,5-triphenyl tetrazolium chloride (TTC) assay under glyphosate-based herbicide stress (Roundup ® Original DI) at concentrations ranging from 0.002 to 7.2 mg mL - 1 . We also assessed the ability of CLV322 to maintain PGPR characteristics in the presence of the herbicide by quantifying indolic compounds, siderophores, and phenazines. The cultivation method significantly influenced the production of metabolites by CLV322, with M3 yielding more consistent results across the evaluated parameters. Our findings suggest that germinating Streptomyces spores for 48 h before introducing glyphosate (M3) enables the analysis of bacterial tolerance to herbicide stress. This methodology may also apply to evaluate other abiotic stresses on Streptomyces strains., Competing Interests: Declarations. Declaration of competing interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Introduction: Death is a natural phenomenon inherent to the human condition and an inevitable consequence of life. As future professionals, nursing students should face the process of death and recognize their limitations, because emotional aspects can influence the quality of health care, especially in Spanish-speaking countries. This study aimed to quantify the level of fear of death among nursing students in a higher education institution in a region of Colombia. Methods: A quantitative correlational study including 258 university students selected by stratified sampling were administered the Collet-Lester Fear of Death Scale; the results were analyzed for the age, religion, marital status, number of children, and academic level of the respondents. Results: On average, the students were 22.9 years old; 83.3% of them were female, 75.6% were Catholic, 14.1% had at least one child, and 66.7% had experienced bereavement in the family. An association was found between the female gender and the fear of one's own death ( p = .025). Conclusion: These findings differ from those reported in other Latin American countries where higher academic level and clinical experience are related to lower fear of death., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In nursing education, contact with real scenarios implies the design of favorable experiences to develop prioritization, reasoning, critical thinking, and management skills that support future practice. In the context of the teaching-learning process, simulation emerges as a support strategy, but its use and management require the knowledge and appropriation of teachers. Clinical simulation during education promotes growth in technical skills and aptitudes such as critical thinking, emotional management, organization, delegation, and teamwork. The culmination positively impacts the student, reflecting on their confidence, security, and adaptability to unexpected or unknown situations and risks., Objective: The aim of this scoping review is to determine the socioemotional skills described during the teaching-learning process mediated by medium- and high-fidelity clinical simulation in nursing students., Methods: The main concepts and limits of the research area will be determined according to the 5 phases of a scoping review proposed by Arksey and O'Malley. Research articles and postgraduate theses published between 2010 and 2023 in English and Spanish will be considered. Dissertation-type documents, book chapters, editorials, abstracts, and articles focused on clinical simulation among nursing professionals will be excluded. The articles will be retrieved from databases available at the Universidad Cooperativa de Colombia, along with CINAHL, Scielo, and PubMed. The search strategy will be based on the Population-Concept-Context framework. Article selection will be carried out by 2 independent evaluators who will review titles and abstracts in stage 1 and the full text in stage 2. A database of retrieved articles will be built with the variables of interest. A qualitative thematic analysis will be conducted by 5 independent reviewers to provide an overview of the literature, focusing on identifying similarities and contrasts between studies and contributions related to the aspects of social skills described in nursing students., Results: The investigation has not yet started. The findings aim to focus on variables within the academic environment that, when correlated with the clinical simulation experience, may determine student learning. The working hypothesis is that students who experience greater satisfaction or possess better communication skills also demonstrate superior performance during high-fidelity simulation activities. The most relevant results will be contrasted considering the stated objective and knowledge gaps. Key aspects will also be compared with other reviews addressing related topics such as communication, self-efficacy, and self-confidence. Skills described by other authors that were not considered in the initial literature review will also be mentioned., Conclusions: Educational institutions are responsible for including learning experiences in controlled environments such as medium- and high-fidelity simulation to ensure the acquisition of technical capabilities and additional socioemotional skills. Recognizing and managing emotions is necessary to provide adequate care for users of health care services and for the increased effectiveness of professionals., Trial Registration: Open Science Framework p4ays; https://osf.io/p4ays., International Registered Report Identifier (irrid): PRR1-10.2196/56436., (©Luz Mery Contreras-Ramos, Elveny Laguado Jaimes, Nelly Esperanza Jaimes Carvajal, Marleny Pico Ferreira, Magda Liliana Villamizar-Osorio. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 19.08.2024.)

Introduction and Aims: The first metatarsophalangeal joint arthrodesis is indicated for the treatment of various pathologies as a technique to reduce pain and improve the support of the first radius. Numerous surgical techniques and fixation methods have been described, with the combination of a dorsal plate and an interfragmentary screw being the one that has shown to be the most stable construct in biomechanical studies. Our aim is to analyze the radiological results after metatarsophalangeal arthrodesis of the hallux using a dorsal plate associated or not with an interfragmentary screw. The differences in terms of consolidation rates and complications in patients diagnosed with hallux rigidus, hallux valgus, hallux varus and failure of previous surgeries were evaluated., Material and Methods: A retrospective cohort study of 55 patients with a mean age of 65.10 years in whom a dorsal plate was used was performed. Patients were divided into 2 groups depending on whether or not an interfragmentary screw was used. The minimum follow-up was 6 months after surgery. The assessment of the pre and postoperative radiological results was based on the variation of the hallux angle, the intermetatarsal angle and the dorsal metatarsophalangeal angle of the hallux, as well as the cases of nonunion identified in each study group., Results: The radiological results, statistically significant differences (p<0.05) were only found in the dorsal metatarsophalangeal angle between both study groups. No statistically significant differences were found regarding the radiological evaluation of the pre and postoperative hallux angle and intermetatarsal angle. An equal decrease of each angles was observed in both study groups. Regarding the consolidation rate, statistically significant differences (p<0.05) were found between group A, which associated an interfragmentary screw, presenting a consolidation rate of 92%, and group B, which did not associate an interfragmentary screw, and that presented a union rate of 63%., Conclusions: Hallux metatarsophalangeal arthrodesis of the hallux with a dorsal plate and interfragmentary screw show best results regarding consolidation rate and complications compared to those cases in which an interfragmentary screw was not used., (Copyright © 2023 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Aims: The first metatarsophalangeal joint arthrodesis is indicated for the treatment of various pathologies as a technique to reduce pain and improve the support of the first radius. Numerous surgical techniques and fixation methods have been described, with the combination of a dorsal plate and an interfragmentary screw being the one that has shown to be the most stable construct in biomechanical studies. Our aim is to analyze the radiological results after metatarsophalangeal arthrodesis of the hallux using a dorsal plate associated or not with an interfragmentary screw. The differences in terms of consolidation rates and complications in patients diagnosed with hallux rigidus, hallux valgus, hallux varus and failure of previous surgeries were evaluated., Materials and Methods: A retrospective cohort study of 55 patients with a mean age of 65.10 years in whom a dorsal plate was used was performed. Patients were divided into two groups depending on whether or not an interfragmentary screw was used. The minimum follow-up was 6 months after surgery. The assessment of the pre and postoperative radiological results was based on the variation of the hallux angle, the intermetatarsal angle and the dorsal metatarsophalangeal angle of the hallux, as well as the cases of nonunion identified in each study group., Results: The radiological results, statistically significant differences (p<0.05) were only found in the dorsal metatarsophalangeal angle between both study groups. No statistically significant differences were found regarding the radiological evaluation of the pre and postoperative hallux angle and intermetatarsal angle. An equal decrease of each angles was observed in both study groups. Regarding the consolidation rate, statistically significant differences (p<0.05) were found between group A, which associated an interfragmentary screw, presenting a consolidation rate of 92%, and group B, which did not associate an interfragmentary screw, and that presented a union rate of 63%., Conclusion: Hallux metatarsophalangeal arthrodesis of the hallux with a dorsal plate and interfragmentary screw show best results regarding consolidation rate and complications compared to those cases in which an interfragmentary screw was not used., (Copyright © 2023 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

This study critically reevaluates reported Biginelli-like reactions using a Kamlet-Abboud-Taft-based solvent effect model. Surprisingly, structural misassignments were discovered in certain multicomponent reactions, leading to the identification of pseudo three-component derivatives instead of the expected MCR adducts. Attempts to replicate literature conditions failed, prompting reconsideration of the described MCRs and proposed mechanisms. Electrospray ionization (tandem) mass spectrometry, NMR, melting points, elemental analyses and single-crystal X-ray analysis exposed inaccuracies in reported MCRs and allowed for the proposition of a complete catalytic cycle. Biological investigations using both pure and "contaminated" derivatives revealed distinctive features in assessed bioassays. A new cellular action mechanism was unveiled for a one obtained pseudo three-component adduct, suggesting similarity with the known dihydropyrimidinone Monastrol as Eg5 inhibitors, disrupting mitosis by forming monoastral mitotic spindles. Docking studies and RMSD analyses supported this hypothesis. The findings described herein underscore the necessity for a critical reexamination and potential corrections of structural assignments in several reports. This work emphasizes the significance of rigorous characterization and critical evaluation in synthetic chemistry, urging a careful reassessment of reported synthesis and biological activities associated with these compounds.

Premise: Barriers at different reproductive stages contribute to reproductive isolation. Self-incompatibility (SI) systems that prevent self-pollination could also act to control interspecific pollination and contribute to reproductive isolation, preventing hybridization. Here we evaluated whether SI contributes to reproductive isolation among four co-occurring Opuntia species that flower at similar times and may hybridize with each other., Methods: We assessed whether Opuntia cantabrigiensis, O. robusta, O. streptacantha, and O. tomentosa, were self-compatible and formed hybrid seeds in five manipulation treatments to achieve self-pollination, intraspecific cross-pollination, open pollination (control), interspecific crosses or apomixis, then recorded flowering phenology and synchrony., Results: All species flowered in the spring with a degree of synchrony, so that two pairs of species were predisposed to interspecific pollination (O. cantabrigiensis with O. robusta, O. streptacantha with O. tomentosa). All species had distinct reproductive systems: Opuntia cantabrigiensis is self-incompatible and did not produce hybrid seeds as an interspecific pollen recipient; O. robusta is a dioecious species, which formed a low proportion of hybrid seeds; O. streptacantha and O. tomentosa are self-compatible and produced hybrid seeds., Conclusions: Opuntia cantabrigiensis had a strong pollen-pistil barrier, likely due to its self-incompatibility. Opuntia robusta, the dioecious species, is an obligate outcrosser and probably partially lost its ability to prevent interspecific pollen germination. Given that the self-compatible species can set hybrid seeds, we conclude that pollen-pistil interaction and high flowering synchrony represent weak barriers; whether reproductive isolation occurs later in their life cycle (e.g., germination or seedling survival) needs to be determined., (© 2024 The Authors. American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

We calculate the spectral properties of two related families of non-Hermitian free-particle quantum chains with N-multispin interactions (N=2,3,...). The first family have a Z(N) symmetry and are described by free parafermions. The second have a U(1) symmetry and are generalizations of XX quantum chains described by free fermions. The eigenspectra of both free-particle families are formed by the combination of the same pseudo-energies. The models have a multicritical point with dynamical critical exponent z=1. The finite-size behavior of their eigenspectra, as well as the entanglement properties of their ground-state wave function, indicate the models are conformally invariant. The models with open and periodic boundary conditions show quite distinct physics due to their non-Hermiticity. The models defined with open boundaries have a single conformal invariant phase, while the XX multispin models show multiple phases with distinct conformal central charges in the periodic case.

The dam failure of the Córrego do Feijão Mine (CFM) located in Minas Gerais State, Brazil, killed at least 278 people. In addition, large extensions of aquatic and terrestrial ecosystems were destroyed, directly compromising the environmental and socioeconomic quality of the region. This study assessed the pollution and human health risks of soils impacted by the tailing spill of the CFM dam, along a sample perimeter of approximately 200 km. Based on potential ecological risk and pollution load indices, the enrichments of Cd, As, Hg, Cu, Pb and Ni in soils indicated that the Brumadinho, Mário Campos, Betim and São Joaquim de Bicas municipalities were the most affected areas by the broken dam. Restorative and reparative actions must be urgently carried out in these areas. For all contaminated areas, the children's group indicated an exacerbated propensity to the development of carcinogenic and non-carcinogenic diseases, mainly through the ingestion pathway. Toxicological risk assessments, including acute, chronic and genotoxic effects, on people living and working in mining areas should be a priority for public management and mining companies to ensure effective environmental measures that do not harm human health and well-being over time., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of motor neurons with very few treatment options. We had previously found that motor neuron degeneration in a mouse model of ALS can be delayed by deleting the axon damage sensor MAP3K12 or dual leucine zipper kinase (DLK). However, DLK is also involved in axon regeneration, prompting us to ask whether combining DLK deletion with a way to promote axon regeneration would result in greater motor neuron protection. To achieve this, we used a mouse line that constitutively expresses ATF3, a master regulator of regeneration in neurons. Although there is precedence for each individual strategy in the SOD1G93A mouse model of ALS, these have not previously been combined. By several lines of evidence including motor neuron electrophysiology, histology and behaviour, we observed a powerful synergy when combining DLK deletion with ATF3 expression. The combinatorial strategy resulted in significant protection of motor neurons with fewer undergoing cell death, reduced axon degeneration and preservation of motor function and connectivity to muscle. This study provides a demonstration of the power of combinatorial therapy to treat neurodegenerative disease., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022.)

Excess adipose tissue is associated with basic tastes perception change, which can negatively affect food choices. However, the effect of overweight and obesity on sensory perception is not clearly explained in the literature yielding heterogeneous results. The present investigation aimed to investigate the temporal dominance of sweet taste according to body mass index (BMI) classification in adults during the ingestion of five passion fruit nectar samples prepared with different sucrose concentrations. The temporal dominance of sensations methodology was applied, which allowed the representation of the stimuli assessed in dominance curves, considering a significant difference in Fisher's exact test (p ≤ 0.05). The attributes evaluated were sweet taste, bitter taste, acidic taste, astringency, passion fruit flavor, metallic taste, or none of the previous options. The sensory analysis was performed with the participation of ninety adult consumers, divided into three groups: EG = eutrophic, WG = overweight, and OG = obesity group, according to the BMI classification. Between the groups a difference in the perception of the attribute "sweet taste" was observed: The EG demonstrated perception of the stimulus in food samples at lower sucrose concentrations, whereas WG and OG showed a higher rate of sweet taste dominance in the food samples with higher concentration of sucrose. Overweight and obese individuals have a lower sensory perception of sweet taste and require a greater amount of sucrose to producing sensory dominance of the attribute "sweet taste" when compared to eutrophic individuals. PRACTICAL APPLICATION: Overweight and obese individuals may experience taste perception in foods in a different way. This study investigated the dominance of sweet taste perception in a fruit beverage by adults with adequate weight and overweight. The results of the tests support the hypothesis that obese and nonobese individuals differ in the sweet taste perception, which can help to understand which factors are involved in sensory perception and food consumption, in addition to providing subsidies for the nonalcoholic beverage industry to elaborate products with new alternatives for concentration and/or replacement of sucrose., (© 2023 Institute of Food Technologists.)

The association between social capital and health is under continuous research. Based both on theoretical frameworks and previous empirical studies, the magnitude and sign of this association are ambiguous. Our main goal is to empirically investigate under which conditions is social capital relevant to obtain good or very good self-rated health, while acknowledging that different paths can lead to this outcome. The data used in this study come from the European Social Survey 2018 (47,423 observations for 29 European countries) and fuzzy-set qualitative comparative analysis was adopted. Our results show that neither the presence of social capital (as measured in this study - 'Generalised trust' and/or 'Informal social connections'), nor its absence, is a necessary condition for good or very good self-rated health. While not being necessary, there are contexts where social capital is relevant for health and, whenever it is present, it positively contributes to good or very good self-rated health. However, our results further suggest that social capital alone is not sufficient to be healthy. The relevance of social capital is contingent on the presence, or absence, of other conditions. What works for some individuals does not work for others. And for any given individual, rarely there is only one way to be healthy. Additionally, our findings suggest that the impact of belonging to a minority ethnic group on health might be stronger than what has been hitherto recognised., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: The spring ligament has paramount role in supporting the arches and its fail causes the collapse of the medial longitudinal arc, inducing adult acquired flatfoot deformity. Our aim was to analyze the clinical and radiological outcomes of spring ligament repair and titanium wedges integration used in surgical osteotomies., Material and Methods: We performed a retrospective study of 23 cases with middle ages of 63, diagnosed with adult acquired flatfoot deformity stage IIB in RAM classification after ortho-prosthetic treatment failure, assessing the functional outcomes using the American Orthopedic Foot and Ankle Society scale and the radiological outcomes studying angles variation (talonavicular uncoverage, talo-first metatarsal angle and Meary axis)., Results: The mean preoperative American Orthopedic Foot and Ankle Society score of the sample was 52±10 and the postoperative 88±6 (p<0.05). The radiological outcomes showed a statistically significant improvement., Conclusion: Spring ligament repair associated to bone reconstruction offers large functional and radiological outcomes to adult acquired flatfoot deformity stage IIB treatment. Titanium wedges present an excellent bone integration., (Copyright © 2022 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Aims: The spring ligament has paramount role in supporting the arches and its fail causes the collapse of the medial longitudinal arc, inducing adult acquired flatfoot deformity. Our aim was to analyze the clinical and radiological outcomes of spring ligament repair and titanium wedges integration used in surgical osteotomies., Material and Methods: We performed a retrospective study of 23 cases with middle ages of 63, diagnosed with adult acquired flatfoot deformity stage IIB in RAM classification after ortho-prosthetic treatment failure, assessing the functional outcomes using the American Orthopedic Foot and Ankle Society scale and the radiological outcomes studying angles variation (talonavicular uncoverage, talo-first metatarsal angle and Meary axis)., Results: The mean preoperative American Orthopedic Foot and Ankle Society score of the sample was 52±10 and the postoperative 88±6 (p<0.05). The radiological outcomes showed a statistically significant improvement., Conclusion: Spring ligament repair associated to bone reconstruction offers large functional and radiological outcomes to adult acquired flatfoot deformity stage IIB treatment. Titanium wedges present an excellent bone integration., (Copyright © 2022 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Cardiovascular risk factors have been measured under different conditions, there is some missing information related to specific occupations, such as penitentiary staff which due to their characteristics could have an increased cardiovascular risk. Objective: To determine cardiovascular risk factors on military staff from penitentiary institutions in Santander-Colombia. Methods: Cross-sectional study conducted with 182 workers. Anthropometric parameters, blood pressure, serum lipid profile, and glucose levels were measured. Univariate and bivariate analyses were carried out to establish differences between individuals. Results: Anthropometric and biochemical measures showed that 71.3% participants were overweight or obese, 29.4% presented high blood pressure with increased levels of total cholesterol (27.5%), triglycerides (40.7%), glucose (9.3%), and 84.1% presented low levels of HDL cholesterol. Bivariate analysis found a negative correlation between BMI and HDL cholesterol ( p  < .05) and a positive correlation between BMI with triglycerides ( p  < .01), systolic and diastolic blood pressure (DBP) ( p  < .01). Conclusion: The studied military population presented increased levels of cardiovascular risk in comparison with a similar group in age, gender of nonmilitary individuals. However, it is important to carry out comparative studies between military staff in order to determine the prevalence and other risk predicting factors present in this specific population.

Triple-negative breast cancer (TNBC) constitutes a very aggressive type of breast cancer with few options of cytotoxic chemotherapy available for them. A chemotherapy regimen comprising of doxorubicin hydrochloride and cyclophosphamide, followed by paclitaxel, known as AC-T, is approved for usage as an adjuvant treatment for this type of breast cancer. In this study we aimed to elucidate the role of KIF11 in TNBC progression throughout its inhibition by two synthetic small molecules containing the DHPM core (dihydropyrimidin-2(1H)-ones or -thiones), with the hypothesis that these inhibitors could be an interesting option of antimitotic drug used alone or as adjuvant therapy in association with AC. For this purpose, we evaluated the efficacy of DHPMs used as monotherapy or in combination with doxorubicin and cyclophosphamide, in Balbc-nude mice bearing breast cancer induced by MDA-MB-231, having AC-T as positive control. Our data provide extensive evidence to demonstrate that KIF11 inhibitors showed pronounced antitumor activity, acting in key points of tumorigenesis and cancer progression in in vivo xenograft model of triple negative breast cancer, like down-regulation of KIF11 and ALDH1-A1. Moreover, they didn't show the classic peripheral neuropathy characterized by impaired mobility, as it is common with paclitaxel use. These results suggest that the use of a MAP inhibitor in breast cancer regimen treatment could be a promising strategy to keep antitumoral activity reducing the side effects., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Guido et al.)

Objective: The aims of this cross-sectional study were to evaluate the prevalence of MetS in PsA patients compared with sex- and age-matched healthy controls and to test possible associations with clinical and laboratory variables., Methods: The prevalence of MetS was determined for 76 PsA patients and 76 sex- and age-matched healthy controls, using the criteria of NCEP/ATPIII and Harmonizing, adjusted for South Americans. Multivariate logistic regression analysis was used to identify independent risk factors for MetS., Results: Metabolic syndrome was significantly more prevalent in the PsA group than in the control group (53.9% vs 18.4%, p < 0.001). Psoriatic arthritis was associated with hypertension, diabetes mellitus, increased waist circumference (WC), elevated body mass index, and raised levels of blood glucose and triglycerides. When comparing MetS and non-Mets PsA patients, MetS was not significantly associated with disease activity, skin involvement, or quality of life. In the logistic regression model, the variables independently associated with MetS were use of biologic disease-modifying antirheumatic drugs (p = 0.001), elevated arterial pressure (p = 0.006), age (p = 0.0015), WC (p = 0.004), and low HDL (p = 0.042)., Conclusions: In this study on PsA patients from Northeastern Brazil, MetS was highly prevalent and associated with biologic disease-modifying antirheumatic drugs use, increased WC, and low HDL., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Prostatic cancer (PC) stands out in terms of its occurrence, pathophysiology, and unfavorable prognostics in humans and dogs. Natural drugs bear an integrative potential for conventional antineoplastic treatments. In this context, the bioproducts of Synadenium grantii have been empirically used in different parts of Brazil for the integrative treatment of prostate cancer in humans. However, there is no availability of scientific evidence of the antitumor effects of S. grantii . Therefore, this study aimed to investigate the bioactive compounds in the latex of S. grantii using the high-resolution mass spectrophotometry (HRMS) and to evaluate its cytotoxic effects on primary canine PC cell cultures. Four fragments of phorbol ester were identified as potential bioactive compounds using the HRMS. With the help of an MTT ([3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyltetrazolium bromide]) assay, two canine prostatic carcinoma cell lines (PC 1 and PC2) showed a decrease in the tumor cell count, with an Inhibitory concentration 50 (IC 50 )of 0.8469 and 0.6068 mg/ml, respectively, for PC1 and PC2. In conclusion, the latex of S. grantii contains phorbol esters in its composition, and its aqueous solution has a cytotoxic effect on canine metastatic PC cells in vitro ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Brito, Prado, Araújo, Arnhold, Matos, de Paula, Ramos, Fonseca-Alves and de Moura.)

The nucleus accumbens shell (NAcSh) and the ventral pallidum (VP) are critical for reward processing, although the question of how coordinated activity within these nuclei orchestrates reward valuation and consumption remains unclear. Inhibition of NAcSh firing is necessary for reward consumption, but the source of this inhibition remains unknown. Here, we report that a subpopulation of VP neurons, the ventral arkypallidal (vArky) neurons, project back to the NAcSh, where they inhibit NAcSh neurons in vivo in mice. Consistent with this pathway driving reward consumption via inhibition of the NAcSh, calcium activity of vArky neurons scaled with reward palatability (which was dissociable from reward seeking) and predicted the subsequent drinking behavior during a free-access paradigm. Activation of the VP-NAcSh pathway increased ongoing reward consumption while amplifying hedonic reactions to reward. These results establish a pivotal role for vArky neurons in the promotion of reward consumption through modulation of NAcSh firing in a value-dependent manner.

In this work, we describe the application of a synthetic enzyme (synzyme) as the catalyst to promote the multicomponent synthesis of isoxazol-5(4H)-one derivatives. The catalytic system could be used up to 15 times without any notable loss of its activity. Some derivatives showed fluorescence and their photophysical data were evaluated. The mechanism of the reaction was, for the first time, investigated and, among the three reaction pathway possibilities, only one was operating under the developed conditions. ESI-MS(/MS) allowed for both the simultaneous monitoring of the multicomponent reaction (MCR) and the proposition of a kinetic model to explain the transformation. The kinetic model pointed firmly to only one reaction pathway and helped to discard the other two possibilities. The antimicrobial abilities of all synthesized derivatives against Gram-positive and Gram-negative strains were also evaluated. The abilities of functional chromophores (fluorescent compounds) as live cell-imaging probes were verified and one of the multicomponent adducts could stain early endosomes selectively in bioimaging experiments.

Nucleotide excision repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under-investigated and underdiagnosed, even although an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counseling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. One hundred and eighty-five patients were included, 13 with specific symptoms during foetal life. Arthrogryposis, microcephaly, cataracts, and skin anomalies are the most frequently reported signs in early subtypes. Non ERCC6/CSB or ERCC8/CSA genes are overrepresented compared to later onset cohorts: 19% patients of this cohort presented variants in ERCC1, ERCC2/XPD, ERCC3/XPB or ERCC5/XPG. ERCC5/XPG is even the most frequently involved gene in foetal cases (10/13 cases, [4/7 families]). In this cohort, the mutated gene, the age of onset, the type of disease, severe global developmental delay, IUGR and skin anomalies were associated with earlier death. This large survey focuses on specific symptoms that should attract the attention of clinicians towards early-onset NER diagnosis in foetal and neonatal period, without waiting for the completeness of classical criteria., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In mosquitoes of medical importance, wing shape and size can vary with altitude, an aspect that can influence dispersion and, consequently, their vector capacity. Using geometric morphometry analysis, Aedes aegypti wing size and shape variation of males and females was studied in four altitudes in the second-smallest department in Colombia: 1,200 m (Tebaida), 1,400 m (Armenia), 1,500 m (Calarcá), and 1,700 m (Filandia). Wing shape in males (P < 0.001) and females (P < 0.001) was significantly different through the altitudinal gradient; in turn, wing size in males followed the altitudinal gradient males (R2 = 0.04946, P = 0.0002), females (R2 = 0.0011, P = 0.46). Wing allometry for males (P < 0.001) and females (P < 0.001) was significant. Likewise, the shape and size of the wings of males (P < 0.001) and females (P < 0.001) had significant fluctuating asymmetry. It is concluded that, in a small scale with an altitudinal variation of 500 meters, it is detected that the size and shape of the wings varied in A. aegypti, main vector the agents that cause dengue, chikungunya, and Zika. The fluctuating asymmetry is present in the individuals studied and could be associated with environmental effects caused by vector control campaigns present in some sampling locations., Competing Interests: The authors have declared that no competing interests exist.

The small protein AcrZ in Escherichia coli interacts with the transmembrane portion of the multidrug efflux pump AcrB and increases resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug-binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that chloramphenicol sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate AcrB activity. This mode of regulation by a small protein and lipid may occur for other membrane proteins., Competing Interests: Declaration of Interests The authors declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Unmet healthcare needs have been used to assess access to healthcare. In scenarios of recession and financial constraints on public policies, it is important to identify which factors besides income can be used to mitigate barriers to access. This was the focus of our study on Portugal's case in the wake of the crisis. We used 17,698 observations from the 5th National Health Survey (2014). We analyzed self-reported unmet needs for medical appointments and treatments, dental healthcare, and prescribed medications. We used a bivariate selection model, considering the fact that unmet needs could only be observed in the subsample of individuals that felt the need for healthcare. The risk of unmet needs for healthcare decreased in individuals with higher income and schooling levels and in the elderly and men. Exclusive coverage by the National Health Service increased the risk of unmet dental healthcare needs. The absence of a circle of close friends to whom one can ask for help and lack of trust in others increased the likelihood of unmet healthcare needs. Better health decreased the risk of unmet needs. While income is an important predictor of unmet needs, we found the impact of other factors such as gender, age, and education. Participation in informal groups reduced the likelihood of unmet needs. Individuals with more healthcare needs end up suffering additional risk.

Background: Induction of labor (IL) involves an overload of work in hospitals, as well as increased intervention. Traditionally, the Bishop score (BS) has been used to predict the outcome of a IL, but there is a growing interest in studying the predictive capacity of ultrasound variables., Objective: Validate a pilot predictive model performed by a single observer (Alvarez-Colomo C), based on clinical parameters and ultrasound parameters, that showed a significant association with the IL result, obtaining a correct prediction of vaginal delivery in 82.8%, with 15% false positive (FP). This validation was carried out under the usual conditions of clinical practice by four observers without distinction., Methods: A prospective, observational study was conducted between September 2010-July 2012, recruiting 231 single pregnancies (Group 2), who were to initiate the IL process, according to the methodology and inclusion criteria of the Alvarez-Colomo study (Group 1151 patients). The outcome variable was the method of delivery., Results: Only fetal head-perineal distance (FHPD), cervical length (CL) and BS showed significant association with the result of IL. After applying the logistic regression equation of the pilot study, the model developed by these four observers reached a predictive capacity of 70.74% (FP = 20%). Clinical characteristics were similar in both groups. Statistically significant differences were found between the two groups for: FHPD, posterior cervical angle (PCA) and funnel existence., Conclusion: It has not been possible to validate the mathematical model of Alvarez's study in the daily conditions of clinical practice, probably due to differences in the ultrasound measurement of FHPD.

Unmet healthcare needs (or foregone healthcare) is a widely used intermediate indicator to evaluate healthcare systems attainment since it relates to health outcomes, financial risk protection, improved efficiency and responsiveness to the individuals' legitimate expectations. This paper discusses the ordinary measure of this indicator used so far, prevalence of unmet needs in the whole population, based on the level of healthcare needs among the population. The prevalence of needs and the prevalence of unmet needs among those in need are key aspects that have not yet been fully explored when it comes to foregone healthcare. We break down the ordinary measure into prevalence of needs and prevalence of unmet needs among those in need based on data taken from the European Social Survey 2014. Afterwards, we analyse these different measures in a cross-country perspective. We also discuss the link between them and the implicit relative assessment of healthcare systems considering the whole population and the sub-group of the population aged 65 or more. Comparisons across countries show different attainment levels unveiling varying challenges across European countries, depending on the combination of levels of need and levels of unmet needs for those in need., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This critical review focuses on some key features which determine successful enantioselective catalysed multicomponent reactions (MCRs) and are typically underappreciated in the literature. A critical analysis of this topic is of current interest and the importance of elucidating the reaction mechanism of a MCR, which is usually a neglected task, is a feature of analysis that is aimed at successfully achieving the enantioselective version of the reaction by proper comprehension of the transformation. The key role of noncovalent interactions is another feature analysed along with the transition state (TS) of the key step for the chiral induction of some selected MCRs. In this critical review, the problems of a lack of mechanistic knowledge and the importance of the rational design of new catalytic systems, considering the possible noncovalent interactions aimed towards designing "flexible" and adaptative catalysts to fit the key intermediates and reagents, are discussed in light of new concepts and trends.

This paper examines the determinants of unmet healthcare needs in Europe. Special emphasis is put on the impact of social capital. Data come from the European Social Survey, 2014. Our study includes 32,868 respondents in 20 countries. Because unmet needs are observed only in those individuals who are exposed to, and recognise, the need of medical care, sample selection can be an issue. To address it, we analyse the data using the bivariate sample selection model. When there is no need, there is no assessment of access to healthcare. Accordingly, in this situation, our model assumes that unmet need is unobserved. The magnitude and statistical significance of the error correlation support our modelling strategy. A high proportion (18.4%) of individuals in need in Europe reported unmet needs. Informal connections seem to mitigate barriers to access as well as trust in other people and institutions, particularly in health services. Financial strain still is a strong predictor of unmet needs. Other vulnerable groups include informal carers, minorities and individuals feeling discriminated. Unmet needs might also arise due to persistent needs of healthcare as it seems to be the case of individuals with lower health status and chronic conditions. A result that merits further research concerns the positive impact of civic engagement on unmet needs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Virus Like Particles (VLPs) are devices for RNA packaging, protection and delivery, with utility in fundamental research, drug discovery, and disease treatment. Using E. coli for combined expression and packaging of non-viral RNAs into Qβ VLPs, we investigated the extent of chemical protection conferred by packaging of RNA in VLPs. We also probed relationships between packaging efficiency and RNA size, sequence and intrinsic compaction. We observe that VLP packaging protects RNA against assault by small diffusible damaging agents such as hydroxyl radicals and divalent cations. By contrast, the extent of unmediated cleavage, in the absence of reactive species, is the same for RNA that is free or packaged within VLPs, and is very slow. In vivo packaging of RNA within VLPs appears to be more efficient for intrinsically compact RNAs, such as rRNA, and less efficient for unstructured, elongated RNA such as mRNA. Packaging efficiency is reduced by addition of the ribosome binding site to a target RNA. The Qβ hairpin is necessary but not sufficient for efficient packaging., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Diversity in eukaryotic rRNA structure and function offers possibilities of therapeutic targets. Unlike ribosomes of prokaryotes, eukaryotic ribosomes contain species-specific rRNA expansion segments (ESs) with idiosyncratic structures and functions that are essential and specific to some organisms. Here we investigate expansion segment 7 (ES7), one of the largest and most variable expansions of the eukaryotic ribosome. We hypothesize that ES7 of the pathogenic fungi Candida albicans (ES7 CA ) could be a prototypic drug target. We show that isolated ES7 CA folds reversibly to a native-like state. We developed a fluorescence displacement assay using an RNA binding fluorescent probe, F-neo. F-neo binds tightly to ES7 CA with a K d of 2.5 × 10 -9 M but binds weakly to ES7 of humans (ES7 HS ) with a K d estimated to be greater than 7 μM. The fluorescence displacement assay was used to investigate the affinities of a library of peptidic aminosugar conjugates (PAs) for ES7 CA . For conjugates with highest affinities for ES7 CA (NeoRH, NeoFH, and NeoYH), the lowest dose needed to induce mortality in C. albicans (minimum inhibitory concentration, MIC) was determined. PAs with the lowest MIC values were tested for cytotoxicity in HEK293T cells. Molecules with high affinity for ES7 CA in vitro induce mortality in C. albicans but not in HEK293T cells. The results are consistent with the hypothesis that ESs represent useful targets for chemotherapeutics directed against eukaryotic pathogens.

Background and Objective: Severe oligohydramnios can induce pulmonary hypoplasia. However, the mechanisms by which leaking of fluids cause lung hypoplasia are not well defined. The objective of this study was to characterize a mouse model of pulmonary hypoplasia induced by oligohydramnios., Methods: Amniotic sacs were punctured on E14.5 of gestation. Untouched fetuses were used as control. Pregnancy was allowed to continue until E18.5 in which lung tissue was collected and evaluated for morphometry, proliferation, differentiation, apoptosis, and angiogenesis., Results: Our results found that lung weight, lung to total body weight ratio, and lung water content were reduced in oligohydramnios when compared to controls. In contrast, oligohydramnios did not affect the DNA content. Morphometric studies confirmed that oligohydramnios fetuses had smaller air spaces than control. Interestingly, cells from oligohydramnios fetuses have smaller size and less regular shapes. Oligohydramnios decreased the differentiation of type I epithelial cells and compromised apoptosis and angiogenesis while proliferation was not affected., Conclusions: Although, the smaller size of the lung could be explained by a decreased of lung fluids, our data suggest that increased of external compression secondary to severe oligohydramnios can compromise cell size and interfere with epithelial and endothelial development. Type I epithelial cells could have an unrecognized key role in the differentiation of the distal lung mediated by mechanical signals. Pediatr Pulmonol. 2017;52:746-756. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

We describe here a one pot RNA production, packaging and delivery system based on bacteriophage Qβ. We demonstrate a method for production of a novel RNAi scaffold, packaged within Qβ virus-like particles (VLPs). The RNAi scaffold is a general utility chimera that contains a functional RNA duplex with paired silencing and carrier sequences stabilized by a miR-30 stem-loop. The Qβ hairpin on the 5΄ end confers affinity for the Qβ coat protein (CP). Silencing sequences can include mature miRNAs and siRNAs, and can target essentially any desired mRNA. The VLP-RNAi assembles upon co-expression of CP and the RNAi scaffold in E. coli. The annealing of the scaffold to form functional RNAs is intramolecular and is therefore robust and concentration independent. We demonstrate dose- and time-dependent inhibition of GFP expression in human cells with VLP-RNAi. In addition, we target the 3΄UTR of oncogenic Ras mRNA and suppress Pan-Ras expression, which attenuates cell proliferation and promotes mortality of brain tumor cells. This combination of RNAi scaffold design with Qβ VLP packaging is demonstrated to be target-specific and efficient., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

[This corrects the article DOI: 10.1371/journal.pone.0161920.].

A retrospective study was conducted of the records and panoramic radiographs of 35 patients treated with bisphosphonates (BP) and diagnosed with MRONJ. Panoramic radiography was used for evaluation, by two examiners, the following findings were subject of search: osteolysis (OT), cortical bone erosion (EC), bone sclerosis focal (FS) and diffuse (DS), bone sequestration (BS), thickening of lamina dura (TD), prominence of the inferior alveolar nerve canal (IAN), persisting alveolar sockets (SK), and the presence of a pathological fracture (PF). Medical information and staging were also recorded in order to correlate with radiographic findings. Bone sclerosis was the most frequent alteration, followed by OT and TD. The mandible was more affected than the maxilla. There was no significant difference between genders or significant correlation between the number of injuries with age and duration of BP usage. Considering the association between the radiographic findings and MRONJ staging, EC was predominant in stage 3 and DS in stage 2. IAN and PF demonstrated greater association with stage 3. In conclusion, the higher the clinical staging, the greater the severity of the bone alteration. Panoramic radiographic examination is a useful screening tool in patients submitted to antiresorptive therapy., Competing Interests: The authors declare that they have no conflict of interests.

Background: We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment., Results: Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected., Conclusions: Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease., Competing Interests: The authors have declared that no competing interests exist.

Divergence between prokaryotic and eukaryotic ribosomal RNA (rRNA) and among eukaryotic ribosomal RNAs is focused in expansion segments (ESs). Eukaryotic ribosomes are significantly larger than prokaryotic ribosomes partly because of their ESs. We hypothesize that larger rRNAs of complex organisms could confer increased functionality to the ribosome. Here, we characterize the binding partners of Saccharomyces cerevisiae expansion segment 7 (ES7), which is the largest and most variable ES of the eukaryotic large ribosomal subunit and is located at the surface of the ribosome. In vitro RNA-protein pull-down experiments using ES7 as a bait indicate that ES7 is a binding hub for a variety of non-ribosomal proteins essential to ribosomal function in eukaryotes. ES7-associated proteins observed here cluster into four groups based on biological process, (i) response to abiotic stimulus (e.g., response to external changes in temperature, pH, oxygen level, etc.), (ii) ribosomal large subunit biogenesis, (iii) protein transport and localization, and (iv) transcription elongation. Seven synthetases, Ala-, Arg-, Asp-, Asn-, Leu-, Lys- and TyrRS, appear to associate with ES7. Affinities of AspRS, TyrRS and LysRS for ES7 were confirmed by in vitro binding assays. The results suggest that ES7 in S. cerevisiae could play a role analogous to the multi-synthetase complex present in higher order organisms and could be important for the appropriate function of the ribosome. Thermal denaturation studies and footprinting experiments confirm that isolated ES7 is stable and maintains a near-native secondary and tertiary structure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Itajaí is a port city in southern Brazil with one of the highest incidence and mortality rates from AIDS in the country. The prevalence and incidence of HIV infection were investigated in 1085 of 3196 new HIV-1 infection cases evaluated in the counseling and testing center of Itajaí from January 2002 to August 2008. Recent infections were assessed using the BED™, and pol region sequencing was performed in 76 samples. The prevalence ranged from 3.08% to 6.17% among women and from 10.26% to 17.36% among men. A total of 17% of infections were classified as recent, with annual incidence varying from 1.6% to 4.8 per 100 patient/year among women and from 2.05% to 8.5 per 100 patient/year among men. Pol sequences were obtained from 38 randomly recent infections selected individuals: 71% were infected by subtype C, 24% B, 2% D, and 2% F1. Among 38 subjects with established infection, 76% were subtype C, and 24% B. Transmitted drug resistance was detected in 18.4% of recent infection subjects (7.8% to nucleoside analog reverse-transcriptase inhibitors, 5.2% to non-nucleoside reverse-transcriptase inhibitors, and 5.2% protease inhibitors) and 5.2% of subjects with established infection had nucleoside analog reverse-transcriptase inhibitors resistance. The high prevalence and incidence of HIV infection in this region is unprecedented in studies involving cases evaluated in the counseling and testing centers in Brazil., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

In this paper, we describe a novel synthesized ionically tagged water-soluble artificial enzyme (PI) that can efficiently cleave phosphate esters, with enhanced an ionic liquid effect through cooperative effects for the substrate activation and further nucleophilic reaction. The dephosphorylation reaction with PI was evaluated in the presence and absence of 2-methyl-4(5)-nitroimidazole, showing impressive rate enhancements of up to 2 × 10(6)-fold, ascribed to the imidazolide species known as excellent nucleophiles, and formed favorably at lower pH values in the presence of PI.

Background: The Barcelona Clinic Liver Cancer (BCLC) classification of hepatocellular carcinoma (HCC) has proved useful in the management of HCC patients. However, BCLC-recommended first-line treatment is not always applicable in clinical practice., Objective: We performed a multicentre retrospective analysis of reasons for deviation from first-line treatment in 2008-2012., Methods: One to three-year survival data were analysed using Kaplan-Meier method., Results: A total of 407 consecutive HCC patients (66.6 ± 3 years, 83% male) with cirrhosis were included. Tumours were detected during surveillance in 53% of patients, grouped as Child-Pugh A (67%), B (25%) and C (8%); and BCLC A (including stage 0, 44%), B (26%), C (15%) and D (15%). In 31% of patients, first-line treatment was not feasible (51% in early stages) due to: technical reasons (74%); patient non-conformity (20%); medical decision (3%); and disease progression (3%). One to three-year survival of patients not receiving the recommended first-line treatment was similar to that of patients treated according to BCLC recommendations (log-rank, p = 0.229)., Conclusion: In real-life practice one-third of HCC patients could not receive first-line BCLC treatment. In our cohort of patients, similar short and medium-term survival was observed. Long-term prospective studies are required to determine the best alternative treatment option when BCLC first-line treatment is not feasible.

Background: Breast cancer is a complex heterogeneous disease and is one of the leading causes of death among women. In addressing the need for treatments of this life-threatening illness, we studied 3,4-dihydropyrimidin-2(1H)-one (or thione) derivatives (DHPMs), a class of inhibitor molecules of the Eg5 motor spindle protein that shows pronounced antitumor activity against several cancer cell lines., Methods: An in vitro screening was performed for identification of DHPMs with potent antitumor effects on MCF-7 and MDA-MB-231 cells and the selected DHPMs were evaluated for their inhibitory activity on Eg5 both in silico, using Molecular dynamics, and in vitro Eg5 inhibition assays. Analysis of cell death induction, proliferation, cell cycle and cancer stem cells (CSC) profile were performed by flow cytometry to assess the influence of the selected DPHMs on these important tumor features. Finally, the effects of DHPM treatment on tube formation were evaluated in vitro using HUVEC cells, and in vivo using a model on chorioallantoic membrane (CAM) of fertilized eggs., Results: We identified five DHPMs with pronounced inhibitory activity on Eg5 motor protein interfering with the proper mitotic spindle assembly during cell division. These compounds impair the correct conclusion of cell cycle of the breast cancer cells and showed to be selective for tumor cells. Moreover, DHPMs modulate the CD44(+)/CD24(-) phenotype leading to a decrease in the CSC population in MDA-MB-231 cells, an important effect since CSC are resistant to many conventional cancer therapies and play a pivotal role in tumor initiation and maintenance. This observation was confirmed by the results which demonstrated that DHPM treated cells had impaired proliferation and were unable to sustain angiogenesis events. Finally, the DHMP treated cells were induced to apoptosis, which is one of the most pursued goals in drug development., Conclusions: The results of our study strongly suggest that DHPMs inhibit important tumorigenic features of breast cancer cells leading them to death by apoptosis. These findings firmly point to DHPM molecular architecture as a promising alternative against breast cancer.

Nitroreductases (NRs) and ene-reductases (ERs) both utilize flavin mononucleotide cofactors but catalyze distinct reactions. NRs reduce nitroaromatics, whereas ERs reduce unsaturated C=C double bonds, and these functionalities are known to somewhat overlap. Recent studies on the ER xenobiotic reductase A (XenA) from Pseudomonas putida demonstrated the possibility of increasing NR activity with active site modifications. Structural comparison between NRs and ERs led us to hypothesize that active site cavity size plays an important role in determining enzyme functionality. Residues of ER KYE1 from Kluyveromyces lactis were selected to increase the binding pocket size, compensate for hydrogen bonding pattern changes, and eliminate ER activity. Single variants were screened, and promising mutations were combined. Variant F296A/Y275A showed a 100-fold improvement in NR specific activity over wild-type, and variant H191A/F296A/Y375A exhibited complete conversion to a NR., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To determine the effects of radiotherapy on salivary BPIFA expression and to investigate the role of BPIFA in the development of known radiotherapy side effects., Materials and Methods: Unstimulated whole-mouth saliva was collected from 45 cancer patients (1 week before treatment, during the treatment, and 1 week after completion of radiotherapy) and from 20 controls. BPIFA1 and BPIFA2 expression was detected by western blotting and analyzed along with clinicopathologic data and side effects from the radiotherapy., Results: A facial radiation field was associated with lower salivary flow during and after radiotherapy and correlated with side effects, mainly mucositis. Salivary BPIFA1 expression levels were similar between the control group and the patient group before treatment. On the other hand, BPIFA2 levels were higher in the patient group before treatment compared with the control group. BPIFA concentration was modified by radiotherapy as BPIFA1 levels increased (P = .0081) and BPIFA2 decreased (P < .0001). Higher levels of BPIFA1 were associated with the presence of mucositis (P = .0363) and its severity (P = .0500)., Conclusions: The present study found that levels of BPIFA1 and glycosylated forms of BPIFA2 are affected by radiotherapy, suggesting that these proteins may play a role in the oral microenvironment in irradiated patients with head and neck cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)