Duplications of KIAA1549 and BRAF screening by Droplet Digital PCR from formalin-fixed paraffin-embedded DNA is an accurate alternative for KIAA1549-BRAF fusion detection in pilocytic astrocytomas

Pilocytic astrocytomas represent the most common glioma subtype in young patients and account for 5.4% of all gliomas. They are characterized by alterations in the RAS–MAP kinase pathway, the most frequent being a tandem duplication on chromosome 7q34 involving the BRAF gene, resulting in oncogenic BRAF fusion proteins. BRAF fusion involving the KIAA1549 gene is a hallmark of pilocytic astrocytoma, but it has also been recorded in rare cases of gangliogliomas, 1p/19q co-deleted oligodendroglial tumors, and it is also a common feature of disseminated oligodendroglial-like leptomeningeal neoplasm. In some difficult cases, evidence for KIAA1549-BRAF fusion is of utmost importance for the diagnosis. Moreover, because the KIAA1549-BRAF fusion constitutively activates the MAP kinase pathway, it represents a target for drugs such as MEK inhibitors, and therefore, the detection of this genetic abnormality is highly relevant in the context of clinical trials applying such new approaches. In the present study, we aimed to use the high sensitivity of Droplet Digital PCR (DDPCR™) to predict KIAA1549-BRAF fusion on very small amounts of formalin-fixed paraffin-embedded tissue in routine practice. Therefore, we analyzed a training cohort of 55 pilocytic astrocytomas in which the KIAA1549-BRAF fusion status was known by RNA sequencing used as our gold standard technique. Then, we analyzed a prospective cohort of 40 pilocytic astrocytomas, 27 neuroepithelial tumors remaining difficult to classify (pilocytic astrocytoma versus ganglioglioma or diffuse glioma), 15 dysembryoplastic neuroepithelial tumors, and 18 gangliogliomas. We could demonstrate the usefulness and high accuracy (100% sensitivity and specificity when compared to RNA sequencing) of DDPCR™ to assess the KIAA1549-BRAF fusion from very low amounts of DNA isolated from formalin-fixed paraffin-embedded specimens. BRAF duplication is both necessary and sufficient to predict this fusion in most cases and we propose that this single analysis could be used in routine practice to save time, money, and precious tissue

Familial cancer aggregation and the risk of lung cancer

CONTEXT: Around 90% of lung cancer worldwide is attributable to cigarette smoking, although less than 20% of cigarette smokers develop lung cancer. Other factors such as diet, chronic lung diseases, occupation and possibly environmental agents also contribute to this cancer. Genetic factors seem to play a role in lung cancer, but the precise characteristics influencing lung cancer susceptibility are not known, since genetic factors are easily obscured by the strong environmental determinants of lung cancer, particularly smoking. OBJECTIVE: To estimate the effect that cancer occurrence among first-degree relatives has on the risk of lung cancer. DESIGN: Hospital-based case-control study. SETTING: The metropolitan region of São Paulo, Brazil. PARTICIPANTS: 334 incident lung cancer cases and 578 controls matched by hospitals. MAIN MEASUREMENTS: By means of a structured questionnaire, cases and controls were interviewed about cancer occurrence in first-degree relatives, tobacco smoking, exposure to passive smoking, occupation, migration and socioeconomic status. Non-conditional logistic regression was used to calculate the risk of familial cancer aggregation, the effect of cancer in first-degree relatives and smoking in conjunction, and for controlling confounders. RESULTS: The adjusted odds ratio (OR) revealed a slight, but not statistically significant, excess risk of lung cancer for subjects with a history of lung cancer in relatives (OR 1.21; 95% confidence interval [CI] 0.50 -- 2.92). The same was found among those with a history of other tobacco-related cancers in relatives (OR 1.36; 95% CI 0.87 -- 2.14). A step gradient effect was observed regarding lung cancer risk, in accordance with increases in the number of pack-years of cigarette consumption. An interaction between familial cancer aggregation and tobacco smoking was detected. CONCLUSIONS: A mildly elevated risk of lung cancer among persons with a positive history of lung and other tobacco-related cancers was observed. The finding of an interaction between the variables of familial cancer aggregation and smoking suggests that familial cancer aggregation could be considered as a marker of susceptibility, increasing the risk of lung cancer among smokers. These results improve our knowledge of lung carcinogenesis and can guide future cancer genetic studies.INTRODUÇÃO: Cerca de 90% dos casos de câncer de pulmão no mundo são atribuíveis ao tabagismo, porém menos de 20% dos fumantes desenvolvem câncer de pulmão. Fatores como dieta, doenças pulmonares crônicas, ocupação e, possivelmente, exposições ambientais também têm papel na etiologia desse câncer. Os fatores genéticos parecem influir na ocorrência da doença, mas as características que influenciam a suscetibilidade à neoplasia pulmonar não são precisamente conhecidas, obscurecidas pela forte influência dos fatores ambientais na determinação da doença, particularmente o tabagismo. OBJETIVOS: Estimar o efeito da ocorrência de câncer em parentes de primeiro grau no risco de câncer de pulmão. TIPO DE ESTUDO: Estudo caso-controle de base hospitalar. LOCAL: Região Metropolitana de São Paulo. PARTICIPANTES: 334 casos de neoplasia pulmonar e 578 controles emparelhados por hospital. VARIÁVEIS ESTUDADAS: Casos e controles foram entrevistados com respeito ao passado de neoplasias em parentes de primeiro grau, tabagismo, tabagismo passivo, ocupação, migração e status socioeconômico. Utilizou-se a regressão logística não-condicional para calcular o risco de câncer em familiares, o efeito conjunto de câncer em familiares e uso de tabaco, e para controlar potenciais variáveis de confusão. RESULTADOS: O odds ratio (OR) ajustado revelou um discreto excesso de risco para câncer de pulmão, não estatisticamente significante, entre os indivíduos com história de câncer de pulmão na família (OR 1,21; intervalo de confiança de 95% [IC 95%] 0,50 -- 2,92) ou entre aqueles com história de outros cânceres relacionados ao tabaco na família (OR 1,36; IC 95% 0,87 --2,14). Foi observado um efeito dose-resposta positivo para o risco de câncer de pulmão de acordo com o aumento do consumo de cigarros. Detectou-se uma interação entre as variáveis câncer na família e tabagismo. CONCLUSÕES: Observou-se um discreto aumento do risco de câncer de pulmão entre indivíduos com história positiva na família de câncer de pulmão e outros cânceres relacionados ao tabaco. Esses resultados sugerem que a presença de aglomerados de câncer na família pode ser considerada como um marcador de suscetibilidade e aumenta o risco de câncer de pulmão entre os fumantes. A interação detectada entre as variáveis agregadas de câncer na família e tabagismo no risco de câncer de pulmão é uma contribuição no conhecimento dos mecanismos da carcinogênese e poderá orientar futuras pesquisas no campo da genética do câncer.University of São Paulo Public Health School Department of EpidemiologyWorld Health Organization International Agency for Research on Cancer Unit of Environmental Cancer EpidemiologyFederal University of São Paulo Department of Preventive MedicineUNIFESP, Department of Preventive MedicineSciEL

Creative collaboration in citizen science and the evolution of ThinkCamps

This chapter discusses how to harness the potential of creative collaboration through ThinkCamp events – an ‘unconference’ style event with an open and creative environment designed to foster co-creation, co-design and collaborative thinking at key points in the citizen science research cycle. It draws on the authors’ experiences of running (and participating in) creative collaborative events and explores their potential to support inclusive, co-creational approaches to citizen science. Finally, it makes specific recommendations for project initiators, event organisers and policymakers

Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in pilocytic astrocytoma.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Pilocytic astrocytomas occur predominantly in childhood. In contrast to the posterior fossa location, hypothalamo-chiasmatic pilocytic astrocytomas display a worse prognosis often leading to multiple surgical procedures and/or several lines of chemotherapy and radiotherapy to achieve long-term control. Hypothalamo-chiasmatic pilocytic astrocytomas and cerebellar pilocytic astrocytomas have a distinctive gene signature and several differential expressed genes (ICAM1, CRK, CD36, and IQGAP1) are targets for available drugs: fluvastatin and/or celecoxib. RESULTS: Quantification by RT-Q-PCR of the expression of these genes was performed in a series of 51 pilocytic astrocytomas and 10 glioblastomas: they were all significantly overexpressed in hypothalamo-chiasmatic pilocytic astrocytomas relative to cerebellar pilocytic astrocytomas, and CRK and ICAM1 were significantly overexpressed in pilocytic astrocytomas versus glioblastomas.We used two commercially available glioblastoma cell lines and three pilocytic astrocytoma explant cultures to investigate the effect of celecoxib/fluvastatin alone or in combination. Glioblastoma cell lines were sensitive to both drugs and a combination of 100 μM celecoxib and 240 μM fluvastatin was the most synergistic. This synergistic combination was used on the explant cultures and led to massive cell death of pilocytic astrocytoma cells.As a proof of concept, a patient with a refractory multifocal pilocytic astrocytoma was successfully treated with the fluvastatin/celecoxib combination used for 18 months. It was well tolerated and led to a partial tumor response. CONCLUSION: This study reports evidence for new targets and synergistic effect of celecoxib/fluvastatin combination in pilocytic astrocytoma. Because it is non-toxic, this new strategy offers hope for the treatment of patients with refractory pilocytic astrocytoma

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine

A recurrent CNN for online object detection on raw radar frames

Automotive radar sensors provide valuable information for advanced driving assistance systems (ADAS). Radars can reliably estimate the distance to an object and the relative velocity, regardless of weather and light conditions. However, radar sensors suffer from low resolution and huge intra-class variations in the shape of objects. Exploiting the time information (e.g., multiple frames) has been shown to help to capture better the dynamics of objects and, therefore, the variation in the shape of objects. Most temporal radar object detectors use 3D convolutions to learn spatial and temporal information. However, these methods are often non-causal and unsuitable for real-time applications. This work presents RECORD, a new recurrent CNN architecture for online radar object detection. We propose an end-to-end trainable architecture mixing convolutions and ConvLSTMs to learn spatio-temporal dependencies between successive frames. Our model is causal and requires only the past information encoded in the memory of the ConvLSTMs to detect objects. Our experiments show such a method's relevance for detecting objects in different radar representations (range-Doppler, range-angle) and outperform state-of-the-art models on the ROD2021 and CARRADA datasets while being less computationally expensive.Comment: 11 pages, 4 figures, 5 table

Heterologous expression of the avirulence gene ACE1 from the fungal rice pathogen Magnaporthe oryzae

The ACE1 and RAP1 genes from the avirulence signalling gene cluster of the rice blast fungus Magnaporthe oryzae were expressed in Aspergillus oryzae and M. oryzae itself. Expression of ACE1 alone produced a polyenyl pyrone (magnaporthepyrone), which is regioselectively epoxidised and hydrolysed to give different diols, 6 and 7, in the two host organisms. Analysis of the three introns present in ACE1 determined that A. oryzae does not process intron 2 correctly, while M. oryzae processes all introns correctly in both appressoria and mycelia. Co-expression of ACE1 and RAP1 in A. oryzae produced an amide 8 which is similar to the PKS-NRPS derived backbone of the cytochalasans. Biological testing on rice leaves showed that neither the diols 6 and 7, nor amide 8 was responsible for the observed ACE1 mediated avirulence, however, gene cluster analysis suggests that the true avirulence signalling compound may be a tyrosine-derived cytochalasan compound.Government of Egypt ScholarshipThe School of Chemistry at the University of Bristol and the Mark Evans ScholarshipKano State Government NigeriaMacArthur FoundationBayero UniversityNigerian Petroleum Technology FundMalaysian Govenment ScholarshipEP/F066104/

Nonmalignant respiratory disease mortality among woodworkers participating in the American Cancer Society Cancer Prevention Study-II (CPS-II)

Nonmalignant respiratory disease (NMRD) mortality was examined among woodworkers participating in the American Cancer Society’s CPS-II cohort study. During the 6-year prospective follow-up, there were 97 NMRD deaths among 11,541 men reporting employment in wood-related occupations and 1,338 NMRD deaths among 317,424 men reporting no exposure to wood dust or wood-related jobs. Relative risks, adjusted for age and smoking, were calculated using Poisson regression. A small excess of NMRD was observed among woodworkers. However, the relative risk was higher among woodworkers who did not report exposure to wood dust (RR = 1.52, 95% CI = 1.18–1.97) than those who did (RR = 1.27, 95% CI = 0.91–1.77), and no clear trend with duration of exposure was observed. An excess of NMRD was observed among woodworkers reporting exposure to asbestos (RR = 1.59, 95% CI = 0.85–2.96), as well as the small number of woodworkers reporting exposure to formaldehyde (RR = 1.95, 95% CI = 0.63–6.06), but men not reporting exposure to these substances also had an excess risk. Although limited by a short follow-up period and crude indicators of exposure, the strengths of this analysis were the ability to compare woodworkers to a similar, healthy population and to adjust for the effects of smoking. Cohort studies with better exposure information are needed to examine the role of occupational exposures among woodworkers in the etiology of respiratory disease

A genetic intervention.

A tool that analyzes the genome of parasites found in the blood of malaria patients can help inform policy decisions on how best to tackle the rise in drug-resistant infections