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Somatic gain-of-function (GOF) mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), the catalytic subunit of phosphoinositide 3-kinase (PI3K), have been recently discovered in cerebral cavernous malformations (CCMs), raising the possibility that the activation of PI3K pathways is a possible universal regulator of vascular morphogenesis. However, there have been contradicting data presented among various groups and studies. To enhance the current understanding of vascular anomalies, it is essential to explore this possible relationship between altered PI3K signalling pathways and its influence on the pathogenesis of CCMs. GOF PIK3CA-mutants have been linked to overgrowth syndromes, allowing this group of disorders, resulting from somatic activating mutations in PIK3CA, to be collectively named as PIK3CA-related overgrowth spectrum disorders. This paper reviews and attempts to conceptualise the relationships and differences among clinical presentations, genotypic and phenotypic correlations and possible coexistence of PIK3CA and CCM mutations/phenotypes in CCM lesions. Finally, we present a model reflecting our hypothetical understanding of CCM pathogenesis based on a systematic review and conceptualisation of data obtained from other studies.

It is well-known that serum and cellular concentrations of zinc are altered in breast cancer patients. Specifically, there are notable zinc hyper-aggregates in breast tumor cells when compared to normal mammary epithelial cells. However, the mechanisms responsible for zinc accumulation and the consequences of zinc dysregulation are poorly understood. In this review, we detailed cellular zinc regulation/dysregulation under the influence of varying levels of sex steroids and breast cancer tumorigenesis to try to better understand the intricate relationship between these factors based on our current understanding of the CmPn/CmP signaling network. We also made some efforts to propose a relationship between zinc signaling and the CmPn/CmP signaling network.

Cerebral cavernous malformations (CCMs) are neurological disorders that make individuals more susceptible to hemorrhagic stroke. The Mexican-Hispanic population has a higher prevalence of both CCMs and metabolic syndrome (MetS), which is also associated with hemorrhagic stroke. A study was conducted with 184 Mexican-Hispanic CCM subjects and age- and sex-matched Hispanic and non-Hispanic white controls. The CCM cohort had a higher proportion of epilepsy and hemorrhagic stroke but a lower proportion of MetS. Higher blood pressure and fasting glucose levels were observed in the CCM cohort. MetS and epilepsy were associated with increased odds of hemorrhagic stroke among elderly CCM patients, and increased systolic blood pressure was significantly linked to increased odds of hemorrhagic stroke in the CCM cohort. To minimize the risk of hemorrhagic stroke, it is important to manage blood pressure and comorbidities like MetS and epilepsy in CCM patients, particularly those older than 50.

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PurposeThe objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that causes cerebral cavernous malformations (CCMs).MethodsThe nsSNPs within the coding sequence for PTB domain of human CCM2 gene, retrieved from exclusive database search, were analyzed for their functional and structural impact using a series of bioinformatic tools. The effects of the mutations on tertiary structure of the PTB domain in human CCM2 protein were predicted to examine the effect of the nsSNPs on tertiary structure on PTB Cores.ResultsOur mutation analysis, through alignment of protein structures between wildtype CCM2 and mutant, indicated that the structural impacts of pathogenic nsSNPs is biophysically limited to only the spatially adjacent substituted amino acid site with minimal structural influence on the adjacent core of the PTB domain, suggesting both cores are independently functional and essential for proper CCM2 function.ConclusionUtilizing a combination of protein conservation and structure-based analysis, we analyzed the structural effects of inherited pathogenic mutations within the CCM2 PTB domain. Our results indicated that the pathogenic amino acid substitutions lead to only subtle changes locally confined to the surrounding tertiary structure of the PTB core within which it resides, while no structural disturbance to the neighboring PTB core was observed, reaffirming the presence of dual functional cores in the PTB domain.