Search

Cerebral cavernous malformations (CCMs) are abnormal expansions of brain capillaries that increase the risk of hemorrhagic strokes, with CCM1 mutations responsible for about 50% of familial cases. The disorder can cause irreversible brain damage by compromising the blood–brain barrier (BBB), leading to fatal brain hemorrhages. Studies show that progesterone and its derivatives significantly impact BBB integrity. The three CCM proteins (CCM1, CCM2, and CCM3) form the CCM signaling complex (CSC), linking classic and non-classic progesterone signaling within the CmPn network, which is crucial for maintaining BBB integrity. This study aimed to explore the relationship between CCM1 and key pathways of the CmPn signaling network using three mouse embryonic fibroblast lines (MEFs) with distinct CCM1 expressions. Omics and systems biology analysis investigated CCM1-mediated signaling within the CmPn network. Our findings reveal that CCM1 is essential for regulating cellular processes within progesterone-mediated CmPn/CmP signaling, playing a crucial role in maintaining microvessel integrity. This regulation occurs partly through gene transcription control. The critical role of CCM1 in these processes suggests it could be a promising therapeutic target for CCMs.

Background: Cerebral Cavernous Malformations (CCMs) are brain vascular abnormalities associated with an increased risk of hemorrhagic strokes. Familial CCMs result from autosomal dominant inheritance involving three genes: KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). CCM1 and CCM3 form the CCM Signal Complex (CSC) by binding to CCM2. Both CCM1 and CCM2 exhibit cellular heterogeneity through multiple alternative spliced isoforms, where exons from the same gene combine in diverse ways, leading to varied mRNA transcripts. Additionally, both demonstrate nucleocytoplasmic shuttling between the nucleus and cytoplasm, suggesting their potential role in gene expression regulation as transcription factors (TFs). Due to the accumulated data indicating the cellular localization of CSC proteins in the nucleus and their interaction with progesterone receptors, which serve dual roles as both cellular signaling components and TFs, a question has arisen regarding whether CCMs could also function in both capacities like progesterone receptors. Methods: To investigate this potential, we employed our proprietary deep-learning (DL)-based algorithm, specifically utilizing a biased-Support Vector Machine (SVM) model, to explore the plausible cellular function of any of the CSC proteins, particularly focusing on CCM gene isoforms with nucleocytoplasmic shuttling, acting as TFs in gene expression regulation. Results: Through a comparative DL-based predictive analysis, we have effectively discerned a collective of 11 isoforms across all CCM proteins (CCM1-3). Additionally, we have substantiated the TF functionality of 8 isoforms derived from CCM1 and CCM2 proteins, marking the inaugural identification of CCM isoforms in the role of TFs. Conclusions: This groundbreaking discovery directly challenges the prevailing paradigm, which predominantly emphasizes the involvement of CSC solely in endothelial cellular functions amid various potential cellular signal cascades during angiogenesis.

BackgroundClinical pharmacy plays an integral role in optimizing inpatient care. Nevertheless, prioritising patient care remains a critical challenge for pharmacists in a hectic medical ward. In Malaysia, clinical pharmacy practice has a paucity of standardized tools to prioritise patient care.AimOur aim is to develop and validate a pharmaceutical assessment screening tool (PAST) to guide medical ward pharmacists in our local hospitals to effectively prioritise patient care.MethodThis study involved 2 major phases; (1) development of PAST through literature review and group discussion, (2) validation of PAST using a three-round Delphi survey. Twenty-four experts were invited by email to participate in the Delphi survey. In each round, experts were required to rate the relevance and completeness of PAST criteria and were given chance for open feedback. The 75% consensus benchmark was set and criteria with achieved consensus were retained in PAST. Experts' suggestions were considered and added into PAST for rating. After each round, experts were provided with anonymised feedback and results from the previous round.ResultsThree Delphi rounds resulted in the final tool (rearranged as mnemonic 'STORIMAP'). STORIMAP consists of 8 main criteria with 29 subcomponents. Marks are allocated for each criteria in STORIMAP which can be combined to a total of 15 marks. Patient acuity level is determined based on the final score and clerking priority is assigned accordingly.ConclusionSTORIMAP potentially serves as a useful tool to guide medical ward pharmacists to prioritise patients effectively, hence establishing acuity-based pharmaceutical care.

Competing Interests: The authors declare no conflict of interest.