REV3 promotes cellular tolerance to 5-fluorodeoxyuridine by activating translesion DNA synthesis and intra-S checkpoint.

The drug floxuridine (5-fluorodeoxyuridine, FUdR) is an active metabolite of 5-Fluorouracil (5-FU). It converts to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP), which on incorporation into the genome inhibits DNA replication. Additionally, it inhibits thymidylate synthase, causing dTMP shortage while increasing dUMP availability, which induces uracil incorporation into the genome. However, the mechanisms underlying cellular tolerance to FUdR are yet to be fully elucidated. In this study, we explored the mechanisms underlying cellular resistance to FUdR by screening for FUdR hypersensitive mutants from a collection of DT40 mutants deficient in each genomic maintenance system. We identified REV3, which is involved in translesion DNA synthesis (TLS), to be a critical factor in FUdR tolerance. Replication using a FUdR-damaged template was attenuated in REV3-/- cells, indicating that the TLS function of REV3 is required to maintain replication on the FUdR-damaged template. Notably, FUdR-exposed REV3-/- cells exhibited defective cell cycle arrest in the early S phase, suggesting that REV3 is involved in intra-S checkpoint activation. Furthermore, REV3-/- cells showed defects in Chk1 phosphorylation, which is required for checkpoint activation, but the survival of FUdR-exposed REV3-/- cells was further reduced by the inhibition of Chk1 or ATR. These data indicate that REV3 mediates DNA checkpoint activation at least through Chk1 phosphorylation, but this signal acts in parallel with ATR-Chk1 DNA damage checkpoint pathway. Collectively, we reveal a previously unappreciated role of REV3 in FUdR tolerance.

Floxuridine supports UPS independent of germline signaling and proteostasis regulators via involvement of detoxification in C. elegans.

The ubiquitin-proteasome system (UPS) is critical for maintaining proteostasis, influencing stress resilience, lifespan, and thermal adaptability in organisms. In Caenorhabditis elegans, specific proteasome subunits and activators, such as RPN-6, PBS-6, and PSME-3, are associated with heat resistance, survival at cold (4°C), and enhanced longevity at moderate temperatures (15°C). Previously linked to improving proteostasis, we investigated the impact of sterility-inducing floxuridine (FUdR) on UPS functionality under proteasome dysfunction and its potential to improve cold survival. Our findings reveal that FUdR significantly enhances UPS activity and resilience during proteasome inhibition or subunit deficiency, supporting worms' normal lifespan and adaptation to cold. Importantly, FUdR effect on UPS activity occurs independently of major proteostasis regulators and does not rely on the germ cells proliferation or spermatogenesis. Instead, FUdR activates a distinct detoxification pathway that supports UPS function, with GST-24 appearing to be one of the factors contributing to the enhanced activity of the UPS upon knockdown of the SKN-1-mediated proteasome surveillance pathway. Our study highlights FUdR unique role in the UPS modulation and its crucial contribution to enhancing survival under low-temperature stress, providing new insights into its mechanisms of action and potential therapeutic applications.

High-load nanoparticles with a chemotherapeutic SN-38/FdUMP drug cocktail.

[Gd(OH)]2+[(SN-38)0.5(FdUMP)0.5]2- inorganic-organic hybrid nanoparticles (IOH-NPs) with a chemotherapeutic cocktail of ethyl-10-hydroxycamptothecin (SN-38, active form of irinotecan) and 5-fluoro-2'-deoxyuridine-5'-phosphate (FdUMP, active form of 5'-fluoruracil), 40 nm in size, are prepared in water. The IOH-NPs contain a total drug load of 63 wt% with 33 wt% of SN-38 and 30 wt% of FdUMP. Cell-based assays show efficient cellular uptake and promising anti-tumour activity on two pancreatic cancer cell lines of murine origin (KPC, Panc02). Beside the high-load drug cocktail, especially the option to use SN-38, which - although 100- to 1000-times more potent than irinotecan - is usually unsuitable for systemic administration due to poor solubility, low stability, and high toxicity upon non-selective delivery. The [Gd(OH)]2+[(SN-38)0.5(FdUMP)0.5]2- IOH-NPs are a new concept to deliver a drug cocktail with SN-38 and FdUMP directly to the tumour, shielded in a nanoparticle, to reduce side effects.

Development of a Supermolecular Radionuclide-Drug Conjugate System for Integrated Radiotheranostics for Non-small Cell Lung Cancer.

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.

Physicochemical Properties of a Methacrylate-Based Dental Adhesive Incorporated with Epigallocatechin-3-gallate

This study aimed to evaluate the influence of epigallocatechin-3-gallate (EGCG) incorporation on the physicochemical properties of a methacrylate-based dental adhesive. EGCG was added to Adper Easy One (3M-ESPE) except in control group, to obtain concentrations of 0.01% w/w and 0.1% w/w of EGCG-doped adhesives. For water sorption (WS) and solubility (SL) surveys, resin discs were assayed following ISO recommendations (n=10). The degree of conversion (DC) was analyzed by FTIR whereas flexural strength (FS) was tested by three-point bending with bar specimens (n=10). Data were subjected to one-way ANOVA and Tukey's test (p<0.05). No significant difference in the DC, WS and FS were found between the different concentrations of EGCG (p>0.05). Adhesives containing 0.1% or 0.01% of EGCC demonstrated similar values of SL (p>0.05) and higher than those found for adhesive without EGCC (p<0.05). In conclusion, the addition of EGCC to adhesive reduced the solubility without affecting the other evaluated properties.

Esse estudo teve como objetivo avaliar a influência da incorporação de epigalocatequina-3-galato (EGCG) nas propriedades físico-químicas de um sistema adesivo à base de metacrilato. O EGCG foi adicionado ao Adper Easy One (3M-ESPE), exceto para o grupo controle, para a obtenção das concentrações de 0,01% e 0,1% p/p. No ensaio de sorção (S) e solubilidade (SL), foram confeccionados discos de resina de acordo com as recomendações da ISO (n=10). O grau de conversão (GC) foi analisado através de FTIR, enquanto a resistência flexural (RF) foi avaliada em teste de flexão de três pontos com espécimes em forma de barra (n=10). Os dados foram submetidos à Análise de Variância a um critério e teste de Tukey (p<0,05). Não houve diferença significativa entre as concentrações de EGCG testadas no GC, SL e RF (p>0,05). Adesivos contendo EGCG a 0,1% ou 0,01% apresentaram valores similares de SL (p>0,05) e maiores do que os valores obtidos pelo adesivo não incorporado por EGCG. Conclui-se que a adição de EGCG ao adesivo reduziu a solubilidade sem afetar as outras propriedades avaliadas.

Las obsesiones antes de Freud: historia y clínica / Obsessions before Freud: history and clinical practice

Se analiza el significado del concepto de “obsesión” en el alienismo del siglo XIX. Desde el punto de vista clínico, la descripción de Esquirol fue completada por otros autores (Jules Falret, Legrand du Saulle). En el ámbito de la reflexión psicopatológica, el alienismo francés, con el delirio emotivo de Morel o la psicastenia de Janet, defendió la teoría emocional, frente al trastorno intelectual propuesto por los médicos alemanes. Finalmente, se insiste en la importancia del marco cultural en la aparición de los síntomas obsesivos y de su interpretación. En este sentido, se estudian las relaciones de los escrúpulos religiosos con la melancolía o la aparición de categorías diagnósticas sometidas a los códigos y mentalidades fin-de-siècle.

The article analyses the significance of the concept of “obsession” in nineteenth-century alienism. From a clinical point of view, Esquirol’s description was completed by other authors (Jules Falret, Legrand du Saulle). In the area of psychopathological studies, French alienism, with Morel’s emotional delirium or Janet’s psychasthenia, defended the emotional theory, as opposed to the intellectual disorder proposed by German doctors. Lastly, the importance of the cultural framework is stressed in the appearance of obsessive symptoms and their interpretation. Along these lines, the article discusses the relationship of religious scruples to melancholy or the appearance of diagnostic categories subject to fin de siècle codes and mentalities.

Retrieval of Trichostrongylus colubriformis infective larvae from grass contaminated in winter and in spring / Recuperação de larvas infectantes de Trichostrongylus colubriformis em gramíneas contaminadas no inverno e na primavera

The survival of infective larvae (L3) of Trichostrongylus colubriformis was evaluated on Brachiaria, Coast-cross and Aruana forage grasses. Feces of sheep parasitized exclusively by T. colubriformis were deposited in winter and spring on experimental plots whose grasses were cut at two heights: 5 cm and 30 cm. One, two, four, eight, 12 and 16 weeks after depositing the feces, fecal and forage samples were collected for the retrieval and quantification of L3. Retrieval of L3 from feces and forage was negligible in winter due to the dry weather, although a few larvae were retrieved in the last larval collections. However, L3 retrieval from fecal samples was greater in spring, especially two weeks after feces were deposited on 30 cm high grasses. At this time, the L3 retrieval rate from the three forage grasses differed significantly (P <0.05), with Aruana grass showing the highest average L3 retrieval rate, followed by Coast-cross and Brachiaria. In conclusion, the winter drought proved very unfavorable for the presence of L3 in the environment, and the microclimate of Aruana pastureland was generally the most favorable for the retrieval of infective larvae.

A sobrevivência de larvas infectantes (L3) de Trichostrongylus colubriformis foi avaliada em pastagem de Braquiária, Coast-cross e Aruana. Fezes de ovinos parasitados exclusivamente por T. colubriformis foram depositadas no inverno e na primavera em parcelas experimentais com duas alturas de corte da forragem, 5 cm e 30 cm. Uma, duas, quatro, oito, 12 e 16 semanas após o depósito, amostras de fezes e de forragem foram coletadas para a recuperação e quantificação de L3. Devido à seca no inverno, a recuperação de L3 das fezes e da forragem foi ínfima, embora tenha havido recuperação de algumas larvas nas últimas coletas. Por outro lado, na primavera houve maior recuperação de L3 das amostras, especialmente duas semanas após a deposição das fezes em meio às pastagens com 30 cm de altura. Nesse momento, houve diferença significativa (P<0,05) entre as três forrageiras, com maior média de L3 no capim Aruana, seguido de Coast-cross e Braquiária. Em conclusão, a seca registrada no período de inverno se mostrou bastante desfavorável à presença de L3 no ambiente e, de forma geral, o microclima da pastagem de Aruana foi o que mais favoreceu a recuperação de larvas infectantes.

Efeito da revascularização renal sobre a evolução da disfunção renal na nefropatia isquêmica aterosclerótica / Effect of renal revascularization on the development of renal dysfunction in atherosclerotic ischemic nephropathy

A doença renal crônica (DRC) é caracterizada por uma perda progressiva da função renal e suas principais causas são hipertensão arterial (HA) e diabete melito. Entre as causas de HA, podemos destacar a doença renal aterosclerótica (DRA). O desenvolvimento de DRC nos pacientes com DRA parece ser decorrente não apenas do acometimento das artérias renais principais, mas também da microcirculação renal, o que pode justificar o fato de o sucesso do procedimento não garantir uma melhora da evolução da DRC. Até o presente momento, não existe evidência de benefício da angioplastia em relação ao tratamento clínico exclusivo nos pacientes com DRA. O presente trabalho analisa os estudos mais significantes sobre os desfechos renais em pacientes portadores de DRA submetidos à revascularização ou ao tratamento clínico exclusivo.

Chronic kidney disease (CKD) is characterized by a progressive loss of renal function and its main causes are hypertension and diabetes mellitus. Among the causes of hypertension is atherosclerotic renal disease (ARD). The development of CKD in patients with ARD appears to be due not only to the involvement of the main renal arteries, but also of the renal microcirculation, which may explain the fact that the success of the procedure does not guarantee an improvement in the progression of CKD. To date there is no evidence of benefit of angioplasty compared to medical treatment alone in patients with ARD. The present paper analyzes the most significant studies on renal outcomes in patients with ARD undergoing revascularization or medical treatment alone.

Adenosina trifosfato bioluminescência para avaliação da limpeza de superfícies: uma revisão integrativa / Adenosine triphosphate bioluminescence to evaluate the effectiveness of surface cleaning: an integrative review / Bioluminiscencia adenosina trifosfato para evaluar la eficacia de la limpieza de superficies: una revisión integrativa

Objetivo: Identificar na literatura indicações e controvérsias do ATP bioluminescência para avaliação da efetividade da limpeza de superfícies em estabelecimentos de saúde. Método: Revisão integrativa da literatura, entre 2000 e 2012, nas bases de dados MEDLINE, LILACS, Science Direct, SCOPUS e Isi Web of Knowledge. Resultados: Selecionou-se para esta revisão 15 artigos. O ATP bioluminescência foi apontado como importante recurso educacional e método complementar à inspeção visual e às análises microbiológicas na avaliação da efetividade da limpeza. A impossibilidade de indicar a contaminação da superfície por micro-organismos viáveis, a interferência por substâncias químicas e a dificuldade de interpretação dos resultados constituem as principais controvérsias para o uso deste nos serviços de saúde. Conclusão: Apesar de constituir importante recurso na avaliação da limpeza de superfícies, mais estudos são necessários para incorporação efetiva do método nos serviços de saúde. .

Objective: To identify indications and controversies in the literature of the use of ATP bioluminescence to evaluate the effectiveness of surface cleaning in healthcare facilities. Method: Integrative literature review between 2000 and 2012 in the following databases: MEDLINE, LILACS, Science Direct, SCOPUS and Isi Web of Knowledge. Results: were selected for this review 15 articles. The ATP bioluminescence was considered an important educational resource and complementary method to visual inspection and microbiological evaluation of the effectiveness of cleaning. The impossibility to indicate surface contamination by microorganisms, interference by chemicals and the difficulty of interpreting the results constitute the main controversies in the use of ATP in health services. Conclusion: Although this is an important resource in the evaluation of surface cleaning, more studies are necessary for effective incorporation of the method in health services. .

Objetivo: Identificar en la literatura las indicaciones y controversias sobre el uso de la bioluminiscencia ATP para evaluar la eficacia de la limpieza de superficies en los servicios de salud. Método: Revisión integrativa de la literatura, entre 2000 y 2012, en las siguientes bases de datos: MEDLINE, LILACS, Science Direct, SCOPUS e ISI Web of Knowledge. Resultados: Se seleccionaron para esta revisión 15 artículos. La bioluminiscencia del ATP se considera un importante recurso educativo y método complementario a la inspección visual y la análisis microbiológica de la evaluación de la efectividad de la limpieza. La imposibilidad de indicar contaminación de la superficie por los microorganismos, la interferencia por los productos químicos y la dificultad de interpretar los resultados constituyen las principales controversias en la utilización de ATP en los servicios de salud. Conclusión: Aunque esto es un elemento importante en la evaluación de limpieza de superficies, se necesitan más estudios para incorporación eficaz del método en los servicios de salud. .

Induccion de sitios fragiles por agentes quimicos y fisicos / Induction of fragile sites by chemical and physical agents

En la actualidad se acepta que muchas neoplasias humanas están causadas por factores y muchos mutágenos químicos inducen aberraciones cormosómicas (AC), las caules se cree que se origina por roturas en zonas cromosómicas específicas o sitios frágiles (SF). Los SF se estudiaron en cultivos de linfocitos expuestos a diversos inductores químicos, pero todavia no se conoce como influyen los factores ambientales en su expresión. Hasta ahora no hay estudios de SF inducidos con rayos X, ni se conoce la interacción de este agente con los inductores quimicos. Este es el primer trabajo que analiza la expresión de SF inducida por rayos X y por 3 inductores de SF: BUDR, FUDR y anfidicolina. Se identificaron 17 bandas cromosómicas significtivamente afectadas (p<0.oo1), que se definieron como SF. Los SF más frecuentes estaban localizados en las bandas 3p14 y 16q23. Se observó un aumento significativo (p<0.01) de AC y SF en el cultivo expuesto a rayos X y en el tratado con FUDR más radiación, indicando la conveniencia de emplear otro agente radiosensibilizador. Los resultados observados sugerirían que muchos SF pueden ser causados por factores ambientales tales como sustancias químicas o radiación. La alta correlación establecida entre los SF y la ubicación de AC inducidos por radiación, AC en cáncer y oncogenes demostraría la importante interacción entre SF, AC y oncogenes en el proceso neoplásico