作者: Bolaños, Elixabet ; Sanmamed, Miguel F ; Rodríguez, Inmaculada ; Melero, Ignacio ; Fernández de Piérola, Eva ; Mínguez, José Ángel ; Herrero-Martin, Claudia ; Chacón, Enrique ; Diez-Caballero, Fernando ; Gomis, Gabriel ; Chiva, Santiago ; Azpilikueta, Arantza ; de Andrea, Carlos ; Teijeira, Álvaro ; Sánchez-Gregorio, Sandra ; Eguren-Santamaría, Iñaki ; Molero-Glez, Paula

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-β. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs. Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors. The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations.

2024-09-01·Journal of Pharmaceutical and Biomedical Analysis

New bioelectrode based on graphene quantum dots-polypyrrole film and Concanavalin A for pathogenic microorganism detection

Article

作者: Santos, Maria P M C ; Oliveira, Maria D L ; de Oliveira, Léony S ; Lima-Neto, Reginaldo G ; Andrade, César A S

Infections caused by microorganisms are a public health problem worldwide. New biodetection systems are essential to diagnose with accuracy resulting in more effective treatment. In this work, we propose a ConA-conjugated graphene quantum dots and polypyrrole film-based biosensor for label-free detection of Candida albicans, Candida glabrata, Candida tropicalis, E. coli, B. subitilis, and S. aureus. We modified polypyrrole and graphene quantum dots (PPY-QDGs) with Concanavalin A (Con A) lectin. ConA is a glucose/mannose-specific lectin. The results showed that ConA lectin has the highest binding affinity for C. tropicalis and S. subtilis. PPY-GQDs-ConA binding profile revealed differential response for Candida spp (C. tropicalis > C. albicans > C. glabrata) and bacterial (B. subtilis > S. aureus > E. coli). The limits of detection (LOD) obtained were 1.42 CFU/mL for C. albicans, and 3.72 CFU/mL for C. glabrata. C. tropicalis yielded a LOD of 0.18 CFU/mL. The respective LODs for the evaluated bacteria were 0.39 CFU/mL for S. aureus, 0.72 CFU/mL for S. subtilis, and 2.63 CFU/mL for E. coli. The differential response obtained for the sensor can be attributed to the heterogeneous distribution of carbohydrates on the microorganism's surfaces. The proposed system based on a flexible substrate is effective for microbiological diagnosis.

2024-08-01·Chemico-Biological Interactions

Concanavalin A, lectin from Canavalia ensiformis seeds has Leishmania infantum antipromastigote activity mediated by carbohydrate recognition domain

Article

作者: Santos-Gomes, Gabriela ; Fonseca, Isabel Pereira da ; Grangeiro, Yasmim Alencar ; Martins, Alice Maria Costa ; Santos, Ana Lúcia Estevam Dos ; Souza, Racquel Oliveira Silva ; Barbosa, Flávia Eduarda Vidal ; Santos, Maria Helena Cruz Dos ; Teixeira, Claudener Souza ; Silva, Cláudio Gleidiston Lima da

Leishmaniases, caused by Leishmania parasites, are widespread and pose significant health risks globally. Visceral leishmaniasis (VL) is particularly prevalent in Brazil, with high morbidity and mortality rates. Traditional treatments, such as pentavalent antimonials, have limitations due to toxicity and resistance. Therefore, exploring new compounds like lectins is crucial. Concanavalin A (ConA) has shown promise in inhibiting Leishmania growth. This study aimed to evaluate its leishmanicidal effect on L. infantum promastigotes and understand its mechanism of action. In vitro tests demonstrated inhibition of promastigote growth when treated with ConA, with IC₅₀ values ranging from 3 to 5 μM over 24-72 h. This study suggests that ConA interacts with L. infantum glycans. Additionally, ConA caused damage to the membrane integrity of parasites and induced ROS production, contributing to parasite death. Scanning electron microscopy confirmed morphological alterations in treated promastigotes. ConA combined with the amphotericin B (AmB) showed synergistic effects, reducing the required dose of AmB, and potentially mitigating its toxicity. ConA demonstrated no cytotoxic effects on macrophages, instead stimulating their proliferation. These findings reinforce that lectin exhibits promising leishmanicidal activity against L. infantum promastigotes, making ConA a potential candidate for leishmaniasis treatment.

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适应症	最高研发状态	国家/地区	公司	日期
β地中海贫血	临床前	美国	Disc Medicine Opco, Inc.	-
血色素沉着症	临床前	美国	Disc Medicine Opco, Inc.	-
骨髓增生异常综合征	临床前	美国	Disc Medicine Opco, Inc.	-