Breast cancer resistance protein (BCRP, ABCG2) is an efflux transporter that plays a crucial role in multidrug resistance to antineoplastic drugs. Ko143, an analogue of the natural product ...fumitremorgin C, is a potent inhibitor of ABCG2 but is rapidly hydrolyzed to an inactive metabolite in vivo. To identify ABCG2 inhibitors with improved metabolic stability, we have assessed a series of Ko143 analogues for their ability to inhibit ABCG2-mediated transport in ABCG2-transduced MDCK II cells and determined the stability of the most potent compounds in liver microsomes. The most promising analogues were evaluated in vivo by positron emission tomography. In vitro, three of the tested analogues were potent ABCG2 inhibitors and stable in microsomes. In vivo, they increased the distribution of the ABCG2/ABCB1 substrate 11Ctariquidar to the brain both in wild-type (with Abcb1a/b transport blocked by tariquidar) and Abcb1a/b(−/−) mice. One analogue was more potent than Ko143 in both animal models.
Purpose
The co-stimulatory molecules CD80 and CD86 are upregulated on activated antigen-presenting cells (APC). We investigated whether local APC activation, induced by subcutaneous (s.c.) ...inoculation of lipopolysaccharides (LPS), can be imaged by positron emission tomography (PET) with CD80/CD86-targeting
64
Cu-labelled abatacept.
Procedures
Mice were inoculated s.c. with extracellular-matrix gel containing either LPS or vehicle (PBS). Immune cell populations were analysed by flow cytometry and marker expression by RT-qPCR.
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Cu-NODAGA-abatacept distribution was analysed using PET/CT and
ex vivo
biodistribution.
Results
The number of CD80
+
and CD86
+
immune cells at the LPS inoculation site significantly increased a few days after inoculation. CD68 and CD86 expression were higher at the LPS than the PBS inoculation site, and CD80 was only increased at the LPS inoculation site. CTLA-4 was highest 10 days after LPS inoculation, when CD80/CD86 decreased again. A few days after inoculation,
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Cu-NODAGA-abatacept distribution to the inoculation site was significantly higher for LPS than PBS (4.2-fold). Co-administration of unlabelled abatacept or human immunoglobulin reduced tracer uptake. The latter reduced the number of CD86
+
immune cells at the LPS inoculation site.
Conclusions
CD80 and CD86 are upregulated in an LPS-induced local inflammation, indicating invasion of activated APCs.
64
Cu-NODAGA-abatacept PET allowed following APC activation over time.
The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron ...emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure–affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, 11CMT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, 11CMT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.
El desarrollo del presente artículo tuvo como objetivo problematizar tres hallazgos adscritos a la triada ciencia-tecnología-sociedad, referenciando los saberes y las prácticas relacionadas con la ...biotecnología y la biología sintética, las cuales instan la optimización de lo vivo y la vida. Estos hallazgos visibilizan los modos de funcionamiento de la biología y la biotecnología como tecnologías de la vida, para lo cual se acudió a las nociones metodológicas de gobierno y contraconductas tomadas de la caja de herramientas de Foucault, dado que estas se focalizan en la búsqueda de soluciones que maximicen el rendimiento humano mediante la aceptación de prácticas relacionadas con la transformación de la vitalidad. Resultado de lo anterior, en el primer hallazgo se indagó por las aplicaciones de la biotecnología; en el segundo, se evidenció el posicionamiento de la biología sintética en el sector industrial; y en el tercero, referente al bioarte, se problematizaron las implicaciones sobre el gobierno de lo vivo y la vida desde una perspectiva económica. En este orden de ideas, el artículo exhorta a la reflexión sobre la biotecnología y la biología sintética como parte de nuestra cotidianidad, lo que amerita la inquietud sobre la aceptación de las prácticas instauradas frente al bienestar humano y del entorno, interpelar las verdades que nos constituyen y pronunciarnos a partir de elecciones personales que develen nuestro posicionamiento ético.
Monoclonal antibodies (mAbs) are a rapidly growing drug class for which great efforts have been made to optimize certain molecular features to achieve the desired pharmacokinetic (PK) properties. One ...approach is to engineer the interactions of the mAb with the neonatal Fc receptor (FcRn) by introducing specific amino acid sequence mutations, and to assess their effect on the PK profile with in vivo studies. Indeed, FcRn protects mAbs from intracellular degradation, thereby prolongs antibody circulation time in plasma and modulates its systemic clearance. To allow more efficient and focused mAb optimization, in vitro input that helps to identify and quantitatively predict the contribution of different processes driving non-target mediated mAb clearance in vivo and supporting translational PK modeling activities is essential. With this aim, we evaluated the applicability and in vivo-relevance of an in vitro cellular FcRn-mediated transcytosis assay to explain the PK behavior of 25 mAbs in rat or monkey. The assay was able to capture species-specific differences in IgG-FcRn interactions and overall correctly ranked Fc mutants according to their in vivo clearance. However, it could not explain the PK behavior of all tested IgGs, indicating that mAb disposition in vivo is a complex interplay of additional processes besides the FcRn interaction. Overall, the transcytosis assay was considered suitable to rank mAb candidates for their FcRn-mediated clearance component before extensive in vivo testing, and represents a first step toward a multi-factorial in vivo clearance prediction approach based on in vitro data.
The prevalence of COPD in Colombia is unknown. This study aimed to investigate COPD prevalence in five Colombian cities and measure the association between COPD and altitude.
A cross-sectional design ...and a random, multistage, cluster-sampling strategy were used to provide representative samples of adults aged ≥ 40 years. Each participant was interviewed (validated Spanish version of the Ferris Respiratory Questionnaire) and performed spirometry before and after 200 μg of inhaled salbutamol, using a portable spirometer according to American Thoracic Society recommendations. COPD definitions were as follows: (1) spirometric: fixed ratio (primary definition): FEV1/FVC < 70% after bronchodilator; (2) medical: a diagnosis of chronic bronchitis, emphysema, or COPD made by a physician; (3) clinical: cough and phlegm ≥ 3 months every year during ≥ 2 consecutive years (chronic bronchitis). Analysis was performed using statistical software.
A total of 5,539 subjects were included. The overall COPD prevalence using the primary definition (spirometric) was 8.9%, ranging from 6.2% in Barranquilla to 13.5% in Medellín. The prevalence measured by the spirometric definition was higher than medical (2.8%) and clinical (3.2%) definitions. After the logistic regression analysis, the factors related with COPD were age ≥ 60 years, male gender, history of tuberculosis, smoking, wood smoke exposure ≥ 10 years, and very low education level. There was a nonsignificant tendency toward larger prevalence with higher altitude.
COPD is an important health burden in Colombia. Additional studies are needed to establish the real influence of altitude on COPD prevalence.
Macrofungi are among the most promising sources of biologically active natural products with nutritional qualities and therapeutic values. In this work, the nutritional value of nine species of wild ...macrofungi from Ibague-Tolima (Colombia) was evaluated. In addition the antioxidant, antimicrobial and cytotoxic activities of an ethanol:water (70:30) extract of wild basidiomata were evaluated. The wild mushrooms' nutritional potential showed that the genus
and
have the best protein percentages, with 18.4% and 18.5%. The nine extracts evaluated managed to stabilize the two radicals evaluated; however, lower IC
was found for
and
extracts. The results showed that
,
and
extracts were the most effective as antimicrobials, with high inhibition percentages against
,
,
and
. Antifungal activity results against
,
sp. and
showed that the nine extracts were effective at the concentrations tested. Considering cell viability against isolated leukocytes, seven of the nine extracts showed percentages higher than 50% of cell viability. This research describes the nutritional value of nine wild macrofungi in Colombia and their potential for antimicrobial, cytotoxic and antioxidant activity.
: climate change is a reality, and more and more people are becoming aware of this global problem, which has generated anxiety in some populations. To validate a short survey to assess eco-anxiety in ...adults in South America.
: It is an instrumental study, and the validation was based on a previous survey, which had six questions and was generated by 217 respondents in the USA in 2021. These questions were subjected to a validation process with expert judgment, pilot and application, and then statistics were obtained. It was validated with 1907 people in six countries in South America, where the mean, standard deviation, skewness and kurtosis were adequate.
: The initial confirmatory factorial model obtained unsatisfactory goodness-of-fit indices, so the indices were modified through a re-specification, where two items were eliminated, after which adequate values were obtained (χ
= 22.34, df = 2,
= 0.00; RMR = 0.020; GFI = 0.990; CFI = 0.990; TLI = 0.990; and RMSEA = 0.070). Finally, the overall Cronbach's α was calculated to be 0.88 (95% CI = 0.86-0.89).
: The test was validated in a large South American population and found that only four questions can efficiently measure anxiety about the effects of climate change. The instrument can be used with other tests to screen different age groups, ethnicities and realities.
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