Project description:Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm and the mitochondrial double membrane. Despite these physical barriers we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements and the features of the fusion fragments indicate that non-homologous end joining and/or replication-dependent DNA double strand break repair are the dominant mechanism involved. This study includes 12 pairs of whole-genome sequences (tumour and paired-normal), which present somatic mitochondrial DNA integrations in tumour genomes. Reference: Young Seok Ju et al., Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells, Genome Research (2015).
Project description:Primary objectives: El objetivo principal del estudio es determinar el tiempo libre de progresión de la enfermedad en los pacientes ancianos sometidos al tratamiento de estudio
Primary endpoints: El parámetro principal de eficacia es tiempo libre de progresión, definido como el tiempo desde el inicio del tratamiento, hasta que se objetiva enfermedad progresiva según los criterios RECIST
Project description:Primary objectives: ? Determinar si el consumo de opiáceos en pacientes tratados con perfusión continua de anestésico local es inferior al consumo de pacientes tratados con perfusión contínua de suero fisiológico
Primary endpoints: 1. Reacción adversa grave a alguno de los fármacos administrados, según criterio clínico.2. Retirada accidental u oclusión de los catéteres3. Infección de la herida quirúrgica. 4. Insuficiencia hepática (aumento de transaminasas, aumento de la bilirrubina y alargamiento del tiempo de protrombina)
En caso de suspensión del estudio, la pauta analgésica a administrar estará constituida por:
? Cirugía de colon: Analgesia con PCA de Cloruro mórfico: bolus de 0,5mg, bloqueo de 5 min. i AINEs pautados? Cirugía hepática: Sistema de PCA : bolus 0,5 mg, bloqueo de 8 min i AINEs pautados.
Project description:Primary objectives: Evaluar la eficacia de altas dosis de irinotecán en el esquema FOLFIRI, en los pacientes con cáncer colorrectal metastásico con genotipo UGT1A1 favorable (homocigoto salvaje *1/*1 y heterocigotos *1/*28)
Primary endpoints: Proporción de respuestas objetivas globales (RR)
Project description:For many decades Indigenous people, including Native Americans and Aboriginal Australians, have fought for their return of their ancient people. By sequencing ten ancient nuclear genomes of Aboriginal Australians and 27 mitogenomes from ancient pre-European Aboriginal Australians (up to 1,540 yr BP) of known provenance we demonstrate the feasibility of successfully identifying the geographic origins of unprovenanced ancestral remains using genomic methods.
Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.
Project description:Primary objectives: Estimar el efecto de la combinación de panitumumab con irinotecán en la tasa de respuesta tumoral, definida como respuesta parcial y completa según los criterios RECIST modificados, en sujetos con CCRm con KRAS no mutado y refractario a la quimioterapia basada en irinotecán
Primary endpoints: Tasa de respuesta objetiva (TRO) durante la fase de tratamiento con terapia combinada.
Project description:Nuclear and mitochondrial organelles must maintain a communication system. Loci on the mitochondrial genome were recently reported to interact with nuclear loci. To determine whether this is part of a DNA based communication system we used genome conformation capture to map the global network of DNA-DNA interactions between the mitochondrial and nuclear genomes (Mito-nDNA) in Saccharomyces cerevisiae cells grown under three different metabolic conditions. The interactions that form between mitochondrial and nuclear loci are dependent on the metabolic state of the yeast. Moreover, the frequency of specific mitochondrial - nuclear interactions (i.e. COX1-MSY1 and Q0182-RSM7) showed significant reductions in the absence of mitochondrial encoded reverse transcriptase machinery. Furthermore, these reductions correlated with increases in the transcript levels of the nuclear loci (MSY1 and RSM7). We propose that these interactions represent an inter-organelle DNA mediated communication system and that reverse transcription of mitochondrial RNA plays a role in this process. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.
Project description:We used SLIC-CAGE to map transcriptional start sites in cortical neurons from Cornelia de Lange Syndrome (CdLS) patients and control individuals. SLIC-CAGE was performed using nuclear RNA isolated from pre-frontal cortical grey matter. Usage of nuclear RNA allows enrichment of unstable RNAs, such as RNA originating from enhancer transcription. We characterised promoter-level gene expression in cortical neurons from CdLS patients and found deregulation of hundreds of genes enriched for neuronal functions.
Project description:We generated high-resolution maps of genome-lamina interactions for different stages of the pre-implantation mouse embryo, including oocyte, zygote, 2cell stage and 8cell stage and additionally mouse ES cells. We find that LAD domains are already present at the zygote stage, but not in the oocyte, concluding that genome-nuclear lamina interactions are not inherited from the maternal germline, but instead are established de novo rapidly after fertilisation. By using a hybrid genetic background, we were able to identify parental-specific genome-nuclear lamina interaction, allowing us to show that the parental genomes have different features, which are globally resolved at the 8-cell stage. We blocked replication in zygotes by treatment with aphidicolin and found that LAD establishment was unaffected. Moreover, we ectopically expressed Kdm5b in zygotes and show that paternal LAD formation is impaired, suggesting that this mechanism is dependent upon de novo H3K4 methylation. Altogether, our data suggest a step-wise assembly model whereby early LAD formation precedes consolidation of TADs and reveals non-inheritance of nuclear organisation from the germline.
