In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new ...(Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.
Hospital-built environment colonization by healthcare-associated infections-related bacteria (HAIrB) and the interaction with their occupants have been studied to support more effective tools for HAI ...control. To investigate HAIrB dynamics and antimicrobial resistance (AMR) profile we carried out a 6-month surveillance program in a developing country public hospital, targeting patients, hospital environment, and healthcare workers, using culture-dependent and culture-independent 16S rRNA gene sequencing methods. The bacterial abundance in both approaches shows that the HAIrB group has important representativeness, with the taxa Enterobacteriaceae,
Pseudomonas
,
Staphylococcus
,
E. coli
, and
A. baumannii
widely dispersed and abundant over the time at the five different hospital units included in the survey. We observed a high abundance of HAIrB in the patient rectum, hands, and nasal sites. In the healthcare workers, the HAIrB distribution was similar for the hands, protective clothing, and mobile phones. In the hospital environment, the healthcare workers resting areas, bathrooms, and bed equipment presented a wide distribution of HAIrB and AMR, being classified as contamination hotspots. AMR is highest in patients, followed by the environment and healthcare workers. The most frequently detected beta-lactamases genes were,
bla
SHV–like
,
bla
OXA–
23
–like
,
bla
OXA–
51
–like
,
bla
KPC–like
,
bla
CTX–M–
1
,
bla
CTX–M–
8
, and
bla
CTX–M–
9
groups. Our results demonstrate that there is a wide spread of antimicrobial resistance due to HAIrB in the hospital environment, circulating among patients and healthcare workers. The contamination hotspots identified proved to be constant over time. In the fight for patient safety, these findings can reorient practices and help to set up new guidelines for HAI control.
Resumo O objetivo do presente estudo foi verificar se os padrões psicométricos da Escala de percepção, por professores, dos comportamentos agressivos de crianças na escola (EPPCACE) evidenciavam sua ...validade interna. No Estudo 1 (n = 210), foi realizada a adaptação do instrumento e executada uma análise fatorial exploratória. No Estudo 2 (n = 203), efetuou-se uma análise fatorial confirmatória. Participaram professores do ensino fundamental de escolas públicas e particulares. Esses responderam à EPPCACE e a perguntas sociodemográficas. Os resultados indicaram que o instrumento é composto por três fatores: Agressividade direcionada ao âmbito geral (α = 0,95), Comportamentos pró-sociais (α = 0,90) e Agressividade direcionada aos professores (α = 0,90). Conclui-se que a EPPCACE é válida e fidedigna, podendo auxiliar na avaliação do contexto escolar a partir da percepção do professor acerca do comportamento agressivo dos alunos.
Resumen El objetivo del presente estudio fue comprobar si los patrones psicométricos de la Escala de percepción de los maestros sobre el comportamiento agresivo de los niños en la escuela (EPPCACE) evidencian su validez interna. En el estudio 1 (n = 210) se realizó la adaptación del instrumento y se ejecutó un análisis factorial exploratorio. En el estudio 2 (n = 203) se efectuó un análisis factorial confirmatorio. Participaron maestros de Enseñanza Primaria de escuelas públicas y privadas. Estos respondieron a la EPPCACE y preguntas sociodemográficas. Los resultados indicaron que el instrumento está compuesto por tres factores: agresividad dirigida al ámbito general (α = 0,95), comportamientos pro-sociales (α = 0,90) y agresividad dirigida a los maestros (α = 0,90). Se concluye que la EPPCACE es válida y fidedigna, pudiendo auxiliar en la evaluación del contexto escolar a partir de la percepción del maestro sobre el comportamiento agresivo de los alumnos.
Abstract The objective of this study was to verify whether the psychometric patterns of the Scale of teachers’ perception of aggressive behavior of children in school (EPPCACE) showed evidence of its internal validity. In Study 1 (n = 210) the instrument was adapted and an exploratory factorial analysis was performed. In Study 2 (n = 203) a confirmatory factorial analysis was performed. Elementary school teachers in public and private schools participated and answered the EPPCACE and sociodemographic questions. Results indicated that the instrument is composed of three factors: Aggressiveness directed to the general scope (α = 0.95), Pro-social behaviors (α = 0.90), and Aggressiveness directed to teachers (α = 0.90). We concluded that the EPPCACE is valid and reliable, and it can help in the evaluation of the school context from the teacher’s perception of the aggressive behavior of the students.
Clinical trials have investigated the effect of probiotics on postsurgical complications in colorectal cancer (CRC). However, so far, there are no systematic reviews evaluating the effect of ...probiotics and synbiotics on the clinical or infectious postsurgical complications of colorectal cancer.
The objective of this review was to synthesize the best available evidence on the effects of the use of probiotics or synbiotics on pre-, peri-, and post-operative complications of CRC surgical resection.
A search of the PubMed, Embase, LILACS, Scopus, Cochrane, Web of Science, ProQuest, and Google Scholar databases was conducted for clinical trials published up until January 2022.
The population characteristics, period and protocol of supplementation, and postoperative complications were extracted and reported. A random-effects model was used to estimate the effect of probiotic and synbiotic treatment on these variables.
In total, 2518 studies were identified, of which 16 were included in the qualitative synthesis and 13 in the meta-analysis. Overall, probiotic supplementation reduced the incidence of ileus (odds ratio OR = .13, 95% confidence interval CI: .02, .78), diarrhea (OR = .32, 95% CI: .15, .69), abdominal collection (OR: .35, 95% CI: .13, .92), sepsis (OR = .41, 95% CI: .22, .80), pneumonia (OR = .39, 95% CI: .19, .83), and surgical site infection (OR = .53, 95% CI: .36, .78). The results of the subgroup analysis indicated that lower dose (<109 colony-forming units), higher duration of supplementation (>14 days), and being administrated ≤5 days before and >10 days after surgery was more effective at reducing the incidence of surgical site infection.
Probiotics and synbiotics seem to be a promising strategy for the prevention of postoperative complications after CRC surgery. Larger, high-quality randomized controlled trials are needed to establish the optimal treatment protocol for the use of probiotics and synbiotics in preventing postoperative complications for CRC surgery.
A presente dissertação tem como principal objetivo a interpretação e
reconstituição hipotéticas das duas fases de construção do balneário romano
das Termas de São Pedro do Sul, partindo da leitura ...crítica da intervenção do
arquiteto João Mendes Ribeiro ao conjunto edificado - o projeto de valorização,
conservação e reabilitação. Este monumento de fundação romana, constitui,
por si só, uma infinidade de temas possíveis de explorar, dos quais nos focamos
em dois fundamentais: o momento da sua fundação e a (re)construção a que
foi sujeito.
A primeira parte - Matéria de Projeto - enquadra o caso de estudo numa
primeira aproximação à sua relação com o sítio - a região de Lafões - e decifra
as questões-base da morfologia do lugar e do meio onde se insere, traçando
a linha cronológica dos momentos históricos que o tornaram na complexa
estrutura dos inícios do século XXI. Por outro lado, estabelece a sua relação
com os aglomerados antigos mais próximos, com as vias e com a presença
estruturante da água - a fonte de água termal e o rio Vouga.
Na segunda parte - O sentido da ruína - apoiamo-nos no cruzamento
dos dados arqueológicos recentes com os antigos, em especial na leitura da
arqueóloga Helena Frade, e construímos um exercício prático, de projeto.
Através da associação de cada elemento de cronologia romana a uma das duas
fases de construção do balneário primitivo e da sua conjugação com a unidade
de medida canónica do império romano - o pes monetalis - levamos a cabo
a interpretação e reconstituição do traçado destas duas fases do balneário
romano e, para a segunda fase, também a reconstituição hipotética da sua
dimensão tridimensional. Deste exercício, segundo apurámos, inédito à data,
identificamos as relações com o traçado urbano contemporâneo, as quais
estarão associadas ao primitivo aglomerado.
Na terceira parte - Atar os fragmentos - fazemos a abordagem ao
projeto de conservação, valorização e reabilitação das termas romanas de São
Pedro do Sul, em jeito de reflexão crítica às intenções de projeto e à intervenção
executada, baseada na procura das respostas a questões de projeto suscitadas
pelo exercício da arquitetura. Fazemos, assim, uma leitura do exterior para o
interior, seguindo o percurso que o aquista contemporâneo será direcionado
a fazer, na qualidade de visitante, e através do qual identificará os momentos
históricos no sentido inverso à cronologia do edifício, isto é, desde a atualidade
até à fundação romana.
The main goal of the present dissertation is a hypothetical interpretation
and re-construction of the two construction phases of the roman baths of São
Pedro do Sul, taking as a starting point the approach established by the architect
João Mendes Ribeiro, at this building.
This monument, of roman foundation, constitutes, by itself, an infinitude
of possible themes to explore, of which we focus on two fundamental: the
foundation moment and (re)construction of the roman bath and the latest
intervention at the set built- the valorization, conservation and rehabilitation
project.
The first part- Matter of project- frames the study case, in a first approach
to its space and relation with the site and unbridles the base questions of
the morphology of the place and the environment where it fits, tracing the
chronological line of the historical moments which made it the complex structure
from the early twenty-first century. On the other hand, it establishes its relation
to the close aggregation, with the ways and water structural presence- at the
thermal water source and Vouga River.
In the second part- The ruins sense - we cross the recent archeological data,
with its bases exposed by the archeologist Helena Frade, and we build a practical
exercise, of project. Through the association of each roman chronological
element to one of the construction phases of the primitive bathhouse and the
conjugation with the canonical unit of measure from the roman empire- o pes
monetalis- it becomes plausible to prosecute the hypothetical interpretation
and reconstruction of the traces from the two roman bathhouse phases and,
to the second phase, also the hypothetical reconstruction of its tridimensional
dimension. From this exercise, unprecedented to date, as investigated, we
identified relation between the urban contemporary trace and the primitive
cluster.
The third part- Connect the fragments - we we approach the conservation,
valorization and rehabilitation project of the roman baths of São Pedro do Sul,
to critically reflect both on the intentions of project and executed intervention.
We explore from the outside to the inside, following the process that the
contemporary user will be directed to do, as a visitant, being able to identify
historical moments since the present days to the roman foundation.
High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, ...such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6
-/-
mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO.
In vitro
, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells.
In vivo
, the multi-targeted treatment improved the antitumor efficacy of the gDE7-based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6
-/-
mice, the combination of gDE7 and 1MT in IL-6
-/-
mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.
The active immunotherapy concept relies on the use of vaccines that are capable of inducing antitumor immunity, reversion of the suppressive immunological environment, and long-term memory responses. ...Previously, antitumor vaccines based on a recombinant plasmid (pgDE7h) or a purified protein (gDE7) led to regression of early-established human papillomavirus (HPV)-associated tumors in a preclinical model. In this work, the anticancer vaccines were combined with cisplatin to treat HPV-induced tumors at advanced growth stages. The antitumor effects were evaluated in terms of tumor regression, induction of specific CD8
T cells, and immune modulation of the tumor microenvironment. Acute toxicity induced by the treatment was measured by weight loss and histological alterations in the liver and kidneys. Our results revealed that the combination of cisplatin with either one of the tested immunotherapies (pgDE7h or gDE7) led to complete tumor regression in mice. Also, the combined treatment resulted in synergistic effects, particularly among mice immunized with gDE7, including activation of systemic and tumor-infiltrating E7-specific CD8
T cells, tumor infiltration of macrophages and dendritic cells, and prevention of tumor relapses at different anatomical sites. Furthermore, the protocol allowed the reduction of cisplatin dosage and its intrinsic toxic effects, without reducing antitumor outcomes. These results expand our knowledge of active immunotherapy protocols and open perspectives for alternative treatments of HPV-associated tumors.
The application of hydrotherapy is growing in the field of animal rehabilitation to improve strength, endurance, fitness, and range of motion, in addition to reducing pain. In the same way, ...land-based activity is recommended for various conditions, including hypertension, muscle atrophy, and obesity. There is a lack of studies that evaluate the safety of incremental exercise in American Pit Bull Terriers. This study assessed the influence of activity on underwater and dry land treadmills on the physiological parameters of dogs. In this regard, 12 adult, male, healthy, and untrained American Pit Bull Terriers were subjected to an incremental exercise test (IET) on the underwater treadmill (Group I) and the dry land treadmill (Group II). Heart rate (HR), respiratory rate (RR), rectal temperature (RT), systolic blood pressure (SBP), and electrocardiographic evaluation, were evaluated before activity (T0), immediately after (T1), 30 min after (T2), and 90 min after the end of exercise (T3), and plasmatic lactate concentrations were measured at T0, T1, and T2 time points. Results obtained were submitted to the Shapiro-Wilk test, ANOVA and Tukey’s test, considering P<0.05. Water activity induced a reduction in RR (P=0.00674) in all examinations after the test on the underwater treadmill and proved to be more demanding than activity on the land treadmill, considering the presence of a deeper and slower RR. Exercise sessions in both groups did not elevate the lactate concentration. The IET can be performed safely on an underwater or dry land treadmill in healthy American Pit Bulls.
RESUMO: A hidroterapia apresenta crescente aplicação no ramo da reabilitação animal, com o intuito de aumentar a força, resistência muscular e amplitude de movimento articular, além de reduzir a dor e melhorar o condicionamento físico do paciente. Assim como a hidroterapia, a atividade desenvolvida em solo é indicada para diversas afecções, inclusive para pacientes hipertensos, com atrofia muscular ou com sobrepeso. São escassos os estudos que avaliam a segurança de testes incrementais em esteira aquática e em esteira seca em American Pit Bull Terriers. Este estudo teve como objetivo avaliar os efeitos da atividade em esteira aquática e em esteira seca sobre os parâmetros fisiológicos de cães. Para isto, cães da raça American Pit Bull Terrier (n=12) machos, adultos, saudáveis e não treinados foram submetidos a teste de esforço incremental (TEI) em hidroesteira com água (Grupo I) e sem água (Grupo II). A frequência cardíaca (FR), frequência respiratória (FR), temperatura retal (TR), pressão arterial sistólica (PAS) e avaliação eletrocardiográfica, foram aferidas antes da atividade (T0), imediatamente após (T1), 30 minutos após (T2) e 90 minutos após o exercício (T3), e a concentração plasmática de lactato foi dosada nos momentos T0, T1 e T2. Os resultados foram submetidos ao teste de Shapiro-Wilk, análise de variância (ANOVA) e pelo Teste de Tukey, considerando significativo o valor de P < 0.05. Houve diminuição da frequência respiratória (P = 0,00674) após a atividade em esteira aquática, que se mostrou mais exigente que a atividade em esteira terrestre, considerando a apresentação de padrão respiratório mais lento e profundo. As sessões de exercício em ambos os grupos não elevaram a concentração de lactato. O teste de esforço incremental em esteira aquática, ou em esteira seca, pode ser desenvolvido com segurança por cães American Pit Bull saudáveis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immunotherapy has become an important ally in the fight against distinct types of cancer. However, the metabolic plasticity of the tumor environment frequently influences the efficacy of therapeutic ...procedures, including those based on immunological tools. In this scenario, immunometabolic adjuvants arise as an alternative toward the development of more efficient cancer therapies. Here we demonstrated that the combination of melatonin, a neuroimmunomodulator molecule, and an indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-DL-tryptophan, DL-1MT) improves the efficacy of an immunotherapy (gDE7) targeting human papillomavirus (HPV)-associated tumors. Melatonin or IDO inhibitors (D-1MT and DL-1MT) directly reduced proliferation, migration, adhesion and viability of a tumor cell line (TC-1), capable to express the HPV-16 E6 and E7 oncoproteins, but could not confer
antitumor protection effects. Nonetheless, combination of gDE7 with melatonin or D-1MT or DL-1MT enhanced the antitumor protective immunity of gDE7-based vaccine in mice. Notably, expression of IDO1 in stromal cells and/or immune cells, but not in tumor cells, inhibited the antitumor effects of the gDE7, as demonstrated in IDO1-deficient mice. Finally, co-administration of gDE7, melatonin and DL-1MT further improved the protective antitumor effects and the numbers of circulating E7-specific CD8
T cells in mice previously transplanted with TC-1 cells. The unprecedented combination of melatonin and IDO inhibitors, as immunometabolic adjuvants, thus, represents a new and promising alternative for improving the efficacy of immunotherapeutic treatments of HPV-associated tumors.
Fungal infections cause 1.7 million deaths annually, which can be attributed not only to fungus-specific factors, such as antifungal resistance and biofilm formation, but also to drug-related ...challenges. In this study, the potential of Amphotericin (AmB) loaded polymeric nanoparticles (AmB-NPs) combined with murine monoclonal antibodies (mAbs) (i.e., CC5 and DD11) was investigated as a strategy to overcome these challenges. To achieve this goal, AmB-NPs were prepared by nanoprecipitation using different polymers (polycaprolactone (PCL) and poly(D,L-lactide) (PLA)), followed by comprehensive characterization of their physicochemical properties and in vitro biological performance. The results revealed that AmB-loaded NPs exhibited no cytotoxicity toward mammalian cells (baby hamster kidney cells-BHK and human monocyte cells-THP-1). Conversely, both AmB-NPs demonstrated a cytotoxic effect against
,
, and
throughout the entire evaluated range (from 10 µg/mL to 0.1 µg/mL), with a significant MIC of up to 0.031 µg/mL. Moreover, the combination of AmB-NPs with mAbs markedly intensified antifungal activity, resulting in a synergistic effect that was two to four times greater than that of AmB-NPs alone. These findings suggest that the combination of AmB-NPs with mAbs could be a promising new treatment for fungal infections that is potentially more effective and less toxic than current antifungal treatments.
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