Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing.

Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient's tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient's tumor identified several therapeutic choices, including Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient's CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient's CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.

Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease.

In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.

Effects of a Supraseasonal Drought on the Ecological Attributes of Plagioscion squamosissimus (Heckel, 1840) (Pisces, Sciaenidae) in a Brazilian Reservoir.

The aim of this study was to evaluate the effect of a supraseasonal drought on the ecological attributes of Plagioscion squamosissimus. The fish were caught quarterly from February 2010 to November 2014 using gill nets in the reservoir of Santa Cruz, Rio Grande do Norte, Brazil. The abundance of the species was evaluated with the catch per unit effort (CPUE) metric and then correlated with the accumulated rainfall and water volume of the reservoir. The diet of the fish was evaluated using the feeding index (IAi). The proportional similarity index (PS i ) was used to evaluate the variation in the niches of the fish. The body condition was inferred through the relative condition factor, and its variation was assessed with ANOVA. A reduction in the abundance of the species that were positively correlated with the reservoir water volume was observed. The diet of the fish comprised shrimp, gastropods, fish, insects, shrimp larvae, and vegetable matter, with shrimp being the major component. PS i showed the occurrence of individual specialization during November 2013 and November 2014. The relative condition factor was not correlated with a reduction in the water volume of the reservoir. The supraseasonal drought did not affect the relative condition factor, diet, and the trophic niche, but it did affect the species abundance.

Food spectrum and seasonal variation of the diet of Plagioscion squamosissimus (Heckel, 1840) (Osteichthyes, Sciaenidae) in Piató Lagoon, Assu, Rio Grande do Norte State, Brazil - DOI: 10.4025/actascibiolsci.v31i3.2140 / Espectro alimentar e variação sazonal da dieta de Plagioscion squamosissimus (Heckel, 1840) (Osteichthyes, Sciaenidae) na lagoa do Piató, Assu, Estado do Rio Grande do Norte, Brasil - DOI: 10.4025/actascibiolsci.v31i3.2140

The diet and seasonal variations in the feeding of Plagioscion squamosissimus were evaluated. Fishes were captured monthly at the Piató Lagoon, Assu, Rio Grande do Norte State, from August of 2004 to July of 2005, examined at a specific time of day. In laboratory, after obtaining the biometric data, fishes were opened and the guts extracted. The stomach contents were analyzed under stereoscopic microscope, and its items were identified and their volume was measured. Occurrence and volumetric frequencies and the food index were calculated. The items were grouped in seven main categories; shrimp and insects were predominant. The item classification made it possible to classify the species as carnivorous with carcinophagous-insectivore tendencies. In respect to seasonal variations, an alteration of the main items was observed according to the seasons, where insects prevailed in the dry season and shrimp stood out in the rainy season. In regards to capture periods, a twilight-nocturnal habit was observed, and activity periods are also marked by differences in the food type consumed, as shrimp prevailed in lower light and insects in brighter times.

Avaliaram-se a dieta e as variações sazonais na alimentação de Plagioscion squamosissimus, capturados mensalmente, na lagoa do Piató, Assu, Estado do Rio Grande do Norte, entre agosto de 2004 e julho de 2005, com despescas em horários específicos. Em laboratório, após a biometria, os peixes foram abertos e eviscerados. Sob microscópio estereoscópico, analisaram-se os conteúdos estomacais, cujos itens, depois de identificados, tiveram o seu volume medido. Foram calculadas as frequências de ocorrência e volumétrica e o índice alimentar. Agruparam-se os itens em sete categorias principais, e camarão e insetos foram as predominantes. A categorização dos itens permitiu classificar a espécie como carnívora com tendência a carcinofagia-insetivoria. Quanto à sazonalidade, observou-se uma alternância dos itens de acordo com as estações do ano: os insetos predominaram na estação seca e o camarão se sobressaiu na estação chuvosa. Considerando os períodos de captura, observou-se hábito crepuscular-noturno, e os horários de atividade também são marcados por diferenças no tipo de alimento consumido, pois o item camarão predominou nas horas de menor luminosidade; o item insetos, nas horas mais claras.

Variability in the caloric content of vascular plants in two Paraná State reservoirs - DOI: 10.4025/actascibiolsci.v26i2.1611 / Variabilidade no conteúdo calórico de plantas vasculares em dois reservatórios do Estado do Paraná - DOI: 10.4025/actascibiolsci.v26i2.1611

The present research aimed to quantify the vascular plants caloric content in two reservoirs in Paraná, as well as the spatial and ecological group variabilities. The sampling was done in December 2002, in the fluvial, transition and lacustrine zones in Rosana and Mourão reservoirs. Aquatic macrophytes and riparian vegetation mature leaves, from different individuals (n=5), belonging to the same species, were randomly sampled. In order to obtain the caloric content, in cal.g-1 dry weight, the samples were pulverized in a ball mill and subjected to combustion in a PARR calorimetric bomb. The data were treated with a null model ANOVA (EcoSim 7.44 program). A wide caloric variability was verified in the vascular plants analysed. Besides, the spatial and ecological group variabilities were significant, so it is not recommended, being use of only one caloric value to these primary producers in energy flow models, necessary a preliminary inspection of the breadth and of the factors that determine such variation

Com o intuito de quantificar o conteúdo calórico das plantas vasculares de dois reservatórios do Estado do Paraná, bem como sua variabilidade espacial e entre grupos ecológicos, foram realizadas amostragens em dezembro de 2002, nas zonas fluvial, de transição e lacustre dos reservatórios Mourão e Rosana. Foram amostradas, ao acaso, folhas maduras de plantas aquáticas e da vegetação ripária de diferentes indivíduos (n = 5), pertencentes à mesma espécie. Para obtenção do conteúdo calórico, em cal.g-1 de peso seco, as amostras foram maceradas em moinho de bola e submetidas à combustão em bomba calorimétrica PARR. Os dados foram submetidos a uma ANOVA modelo nulo, utilizando-se o programa EcoSim versão 7.44. Foi constatado que as plantas vasculares analisadas apresentaram ampla variabilidade calórica. Além disso, foram significativas as variabilidades espacial e entre os grupos ecológicos, não sendo recomendável o uso de um único valor calórico para estes produtores primários em modelos de fluxo de energia, sendo necessária, uma inspeção preliminar da amplitude e dos fatores que são determinantes de tal variação

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.