Establishment of In Vivo Acquired Resistance to Chemotherapy Via Individual Dose Escalation Treatment Regime.

The vast majority of cancer deaths are the result of drug resistance. The lack of superior preclinical models that better reflect the complexity of relapsed disease hinders the development of novel therapeutics. 2D and 3D in vitro cell-based assays have provided some information, but this is limited and does not consider the role of the tumor microenvironment.

A new familial cancer syndrome including predisposition to Wilms tumor and neuroblastoma.

Wilms tumor and neuroblastoma are childhood tumors of the kidney and undifferentiated neural crest cells, respectively. Both disorders are primarily sporadic, but familial Wilms tumor pedigrees and familial neuroblastoma pedigrees are each well recognized and account for approximately 1-3% of each tumor type. Families with Wilms tumor and neuroblastoma in the same, or related individuals, have not been reported.

No evidence for epigenetic inactivation of fumarate hydratase in leiomyomas and leiomyosarcomas.

Germline mutations in Fumarate Hydratase (FH) cause the development of leiomyomas and leiomyosarcomas in the syndromes Multiple Cutaneous and Uterine Leiomyomata (MCUL1) and Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). There is little evidence, however, that FH mutation plays a role in the development of sporadic leiomyomas or leiomyosarcomas. Such observations do not, however, exclude a role for FH in tumour development outside the context of MCUL1/HLRCC, as it is possible that FH expression could be silenced by epigenetic mechanisms.

BRAF mutations are detectable in conjunctival but not uveal melanomas.

Activating mutations in exon 15 of BRAF have been detected in a high proportion of cutaneous melanomas. To determine whether such mutations are a feature of conjunctival or uveal melanomas, we screened DNA from these tumours. Twenty-one conjunctival and 88 uveal tumours were included in the study.

Mutations in PTF1A cause pancreatic and cerebellar agenesis.

Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family.

Overgrowth syndromes: is dysfunctional PI3-kinase signalling a unifying mechanism?

Studies in drosophila and animal models have shown that the phosphoinositide-3-kinase (PI3-kinase) axis plays a central role in normal development, defining the number and size of cells in tissues. Dysfunction of this pathway leads to growth anomalies and has been established to play a key role in the pathogenesis of Cowden syndrome and tuberous sclerosis. It is probable that dysfunction of this pathway is the basis of other disorders especially those typified by asymmetric overgrowth.