Revealing the BRD4-NOTCH3 fusion: A novel hill in the cancer landscape.

OBJECTIVES: Gene fusions are becoming more evident in cancer scenario for either being the driver alterations, or for the great therapeutic target potential in many cases. Our aim was to characterize the BRD4-NOTCH3 fusion correlating with clinical features, and to determine the frequency of this fusion in the oncological population. MATERIAL AND METHODS: One patient diagnosed with lung adenocarcinoma at Hospital Sírio-Libanês (Brazil) was included. Foundation Medicine database was searched for all BRD4-NOTCH3 fusions among 233,804 specimens. RESULTS: A 76-year-old male patient was diagnosed with lung adenocarcinoma. Molecular assessments demonstrated negative ALK and EGFR, with PD-L1 expression positive by 60 %. He was treated with first line chemotherapy and second line immunotherapy. Subsequent treatments resume re-exposures to chemotherapy with poor responses. A next-generation sequencing (NGS) based assay was performed in the tumor biopsy, revealing mainly mutation in STK11, microsatellite stability, TMB-intermediate, MYC amplification and a BRD4-NOTCH3 fusion. The breakpoint analysis of this fusion indicates that BRD4 active domains are preserved, suggesting that it maintained DNA binding activity, as well as its capacity to be halt by BET inhibitors. Foundation Medicine database was searched for all BRD4-NOTCH3 fusions among more than 230-thousand specimens and it was found in 87 new cases in a rate of 0.04 % occurrence in solid tumors, predominately in gynecological cancers. The same rate was found when we analyzed a different dataset. CONCLUSION: In conclusion, this is the first report of the BRD4-NOTCH3 gene fusion associated with clinical characterization and, although rare, the occurrence of this fusion is constant in different population. Our data suggest that this fusion has great potential to targeted-therapy.

Colonization of Wild Blackberry Plants in California by Fusarium oxysporum f. sp. mori.

Fusarium oxysporum f. sp. mori, the causal agent of Fusarium wilt of blackberry, was first reported in California and Mexico in 2016. A limited survey of the population revealed this pathogen to be one of the most diverse formae speciales of F. oxysporum. We explored the possibility that strains of F. oxysporum pathogenic to commercial blackberry could also be recovered from wild blackberry (Rubus spp.) in California. For this purpose, wild Rubus species in blackberry nurseries, fruit production fields, and nearby areas were collected between 2017 and 2019. Thirty-four isolates of F. oxysporum were recovered from asymptomatic Rubus armeniacus and Rubus ursinus plants. Based on sequence of the translation elongation factor 1-α, somatic compatibility, and pathogenicity to blackberry, 16 isolates were confirmed as F. oxysporum f. sp. mori. These isolates were associated with three somatic compatibility groups, one of which was first identified in this study. Recovery of the pathogen confirmed that wild blackberry plants can act as a reservoir of inoculum of F. oxysporum f. sp. mori and that it can move from wild blackberry plants to commercial cultivars or vice versa.

Lethal interactions between parasites and prey increase niche diversity in a tropical community.

Ecological specialization should minimize niche overlap, yet herbivorous neotropical flies (Blepharoneura) and their lethal parasitic wasps (parasitoids) exhibit both extreme specialization and apparent niche overlap in host plants. From just two plant species at one site in Peru, we collected 3636 flowers yielding 1478 fly pupae representing 14 Blepharoneura fly species, 18 parasitoid species (14 Bellopius species), and parasitoid-host associations, all discovered through analysis of molecular data. Multiple sympatric species specialize on the same sex flowers of the same fly host-plant species-which suggests extreme niche overlap; however, niche partitioning was exposed by interactions between wasps and flies. Most Bellopius species emerged as adults from only one fly species, yet evidence from pupae (preadult emergence samples) show that most Bellopius also attacked additional fly species but never emerged as adults from those flies.

Who is stressed? Comparing cortisol levels between individuals.

UNLABELLED: Cortisol is the most commonly used biomarker to compare physiological stress between individuals. Its use, however, is frequently inappropriate. Basal cortisol production varies markedly between individuals. Yet, in naturalistic studies that variation is often ignored, potentially leading to important biases. OBJECTIVES: Identify appropriate analytical tools to compare cortisol across individuals and outline simple simulation procedures for determining the number of measurements required to apply those methods. METHODS: We evaluate and compare three alternative methods (raw values, Z-scores, and sample percentiles) to rank individuals according to their cortisol levels. We apply each of these methods to first morning urinary cortisol data collected thrice weekly from 14 cycling Mayan Kaqchiquel women. We also outline a simple simulation to estimate appropriate sample sizes. RESULTS: Cortisol values varied substantially across women (ranges: means: 1.9-2.7; medians: 1.9-2.8; SD: 0.26-0.49) as did their individual distributions. Cortisol values within women were uncorrelated. The accuracy of the rankings obtained using the Z-scores and sample percentiles was similar, and both were superior to those obtained using the cross-sectional cortisol values. Given the interindividual variation observed in our population, 10-15 cortisol measurements per participant provide an acceptable degree of accuracy for across-women comparisons. CONCLUSIONS: The use of single raw cortisol values is inadequate to compare physiological stress levels across individuals. If the distributions of individuals' cortisol values are approximately normal, then the standardized ranking method is most appropriate; otherwise, the sample percentile method is advised. These methods may be applied to compare stress levels across individuals in other populations and species.

Intraerythrocytic stages of Plasmodium falciparum biosynthesize menaquinone.

Herein, we show that intraerythrocytic stages of Plasmodium falciparum have an active pathway for biosynthesis of menaquinone. Kinetic assays confirmed that plasmodial menaquinone acts at least in the electron transport. Similarly to Escherichia coli, we observed increased levels of menaquinone in parasites kept under anaerobic conditions. Additionally, the mycobacterial inhibitor of menaquinone synthesis Ro 48-8071 also suppressed menaquinone biosynthesis and growth of parasites, although off-targets may play a role in this growth-inhibitory effect. Due to its absence in humans, the menaquinone biosynthesis can be considered an important drug target for malaria.

Um analista do comportamento olha para tratamentos tradicionais de pedófilos e estupradores / A behavior analyst looks at traditional treatment of pedophiles and rapists

O artigo discute o tratamento do comportamento de estupradores e pedófilos de um ponto de vista analítico-comportamental, ou seja, do ponto de vista da relação entre o ambiente de tratamento e as condições em que a violação sexual ocorre. Consideramos a relação entre a resposta tratada na terapia e a resposta que ocorre no ambiente não clínico, os estímulos presentes no ambiente de tratamento e os estímulos presentes no ambiente não clínico, e a relação das conseqüências aplicadas durante a terapia e aquelas que poderiam ocorrer no ambiente não clínico. Além disso, nós especulamos sobre a função que o comportamento verbal pode ter na mudança do comportamento e das condições que devem estar presentes para mudanças no comportamento verbal resultarem em mudanças em comportamento sexualmente ofensivo. Os tratamentos considerados foram: terapia tradicional da fala, sensibilização encoberta, tratamento direto do comportamento precursor em ambientes não clínicos, e prevenção de recaída.(AU)

The paper discusses treatment of the behavior of rapists and pedophiles from a behavior analytic view point. We look at the treatment programs from the standpoint of the relation between the treatment environment and the conditions in which sexual offenses occur. Hence, we consider the relationship between the response treated in therapy and the response occurring in the non-treatment environment, the stimuli present in the treatment environment and the stimuli present in the non-treatment environment, and the relationship of the consequences applied during therapy and those that might occur in the non-treatment environment. Moreover, we speculate about the role that verbal behavior may have in changing behavior and the conditions that must be present for changes in verbal behavior to result in changes in sexually offensive behavior. Among the treatments considered are: traditional talk therapy, covert sensitization, direct treatment of precursor behavior in non-clinical environments, and relapse prevention.(AU)