Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature.

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks

A systematic autopsy survey of human infant bridging veins

In the first years of life, subdural haemorrhage (SDH) within the cranial cavity can occur through accidental and non-accidental mechanisms as well as from birth-related injury. This type of bleeding is the most common finding in victims of abusive head trauma (AHT). Historically, the most frequent cause of SDHs in infancy is suggested to be traumatic damage to bridging veins traversing from the brain to the dural membrane. However, several alternative hypotheses have been suggested for the cause and origin of subdural bleeding. It has also been suggested by some that bridging veins are too large to rupture through the forces associated with AHT. To date, there have been no systematic anatomical studies on infant bridging veins. During 43 neonatal, infant and young child post-mortem examinations, we have mapped the locations and numbers of bridging veins onto a 3D model of the surface of a representative infant brain. We have also recorded the in situ diameter of 79 bridging veins from two neonatal, one infant and two young children at post-mortem examination. Large numbers of veins, both distant from and directly entering the dural venous sinuses, were discovered travelling between the brain and dural membrane, with the mean number of veins per brain being 54.1 and the largest number recorded as 94. The mean diameter of the bridging veins was 0.93 mm, with measurements ranging from 0.05 to 3.07 mm. These data demonstrate that some veins are extremely small and subjectively, and they appear to be delicate. Characterisation of infant bridging veins will contribute to the current understanding of potential vascular sources of subdural bleeding and could also be used to further develop computational models of infant head injury

El gasto social : evolución y estado actual

Fil: Scheimberg, Sebastián A.. Universidad de San Andrés. Departamento de Economía; Argentina

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature.

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks

Cornification defect in the Golden retriever: clinical, histopathological, ultrastructural and genetic characterisation

Veterinarians have recognised a nonpruritic skin disease in the Golden retriever breed characterised by excessive scaling of large, variably pigmented flakes of skin in otherwise healthy dogs. This prospective case series describes clinical, histopathological, ultrastructural and genetic features of this cornification defect in 17 affected dogs. The condition affects young dogs of either sex and is characterised by symmetrical, predominantly ventro-lateral scaling and hyperpigmentation of the trunk. Histopathological and ultrastructural changes of the stratum corneum are suggestive of delayed degradation of corneodesmosomes. A genetic aetiology is proposed and a single-trait autosomal recessive mode of inheritance discussed

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks