Variation in neuroimaging and outcomes in patients with Sturge Weber syndrome Type III.

OBJECTIVES: Sturge Weber syndrome (SWS) is a neurovascular condition with an estimated incidence of 1 in 20,000 to 50,000 live births. SWS Types I and II involve cutaneous and ophthalmological findings, with neurological involvement in Type I. SWS Type III is exclusive to brain stigmata. Our study aims to describe the characteristics of brain MRI findings and report neuroradiological features with seizure and cognitive outcomes in patients with SWS Type III. METHODS: This is a retrospective case series examining the clinical, radiological, and cognitive characteristics of patients with SWS Type III referred to the SWS Clinic at Boston Children's Hospital. We analyzed brain MRI findings based on vascular and parenchymal features. Clinical and cognitive outcomes were based on a validated assessment tool in this population (Neuroscore). RESULTS: This dedicated case series of patients with Type III SWS from a single center identified ten patients. All patients had classic stigmata indicative of SWS. Two distinct radiological phenotypes were found, one characterized by more pronounced deep venous enlargement, and the other, with more pronounced parenchymal abnormalities. There was heterogeneity in seizure presentation and outcome. Earlier age of onset and seizures predict more severe outcomes, as seen in classic SWS. CONCLUSION: We could not find significant divergence in outcomes between patients with differing neuroimaging phenotypes. These results raise the question of whether the two distinct radiological phenotypes found in SWS Type III are reflective of different disease entities, with underlying genetic heterogeneity. These results suggest the need for larger, multi-center natural history studies.

CDC7 inhibition drives an inflammatory response and a p53-dependent senescent-like state in breast epithelial cells.

Drugs that block DNA replication prevent cell proliferation, which may result in anticancer activity. The latter is dependent on the drug's mode of action as well as on cell type-dependent responses to treatment. The inhibition of Cell division cycle 7-related protein kinase (CDC7), a key regulator of DNA replication, decreases the efficiency of origin firing and hampers the restarting of paused replication forks. Here, we show that upon prolonged CDC7 inhibition, breast-derived MCF10A cells progressively withdraw from the cell cycle and enter a reversible senescent-like state. This is characterised by the rewiring of the transcriptional programme with the induction of cytokine and chemokine expression and correlates with the accumulation of Cyclic GMP-AMP synthase (cGAS)-positive micronuclei. Importantly, cell fate depends on Cellular tumour antigen p53 (p53) function as cells no longer enter senescence but are funnelled into apoptosis upon p53 knockout. This work uncovers key features of the secondary response to CDC7 inhibitors, which could aid the development of these compounds as anticancer drugs.

PTBP1 enforces ATR-CHK1 signaling determining the potency of CDC7 inhibitors.

CDC7 kinase is crucial for DNA replication initiation and fork processing. CDC7 inhibition mildly activates the ATR pathway, which further limits origin firing; however, to date the relationship between CDC7 and ATR remains controversial. We show that CDC7 and ATR inhibitors are either synergistic or antagonistic depending on the degree of inhibition of each individual kinase. We find that Polypyrimidine Tract Binding Protein 1 (PTBP1) is important for ATR activity in response to CDC7 inhibition and genotoxic agents. Compromised PTBP1 expression makes cells defective in RPA recruitment, genomically unstable, and resistant to CDC7 inhibitors. PTBP1 deficiency affects the expression and splicing of many genes indicating a multifactorial impact on drug response. We find that an exon skipping event in RAD51AP1 contributes to checkpoint deficiency in PTBP1-deficient cells. These results identify PTBP1 as a key factor in replication stress response and define how ATR activity modulates the activity of CDC7 inhibitors.

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage.

The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11-dependent degradation in BRCA2-deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference.

Quantifying patient preferences for symptomatic breast clinic referral: a decision analysis study.

OBJECTIVES: Decision analysis study that incorporates patient preferences and probability estimates to investigate the impact of women's preferences for referral or an alternative strategy of watchful waiting if faced with symptoms that could be due to breast cancer. SETTING: Community-based study. PARTICIPANTS: Asymptomatic women aged 30-60 years. INTERVENTIONS: Participants were presented with 11 health scenarios that represent the possible consequences of symptomatic breast problems. Participants were asked the risk of death that they were willing to take in order to avoid the health scenario using the standard gamble utility method. This process was repeated for all 11 health scenarios. Formal decision analysis for the preferred individual decision was then estimated for each participant. PRIMARY OUTCOME MEASURE: The preferred diagnostic strategy was either watchful waiting or referral to a breast clinic. Sensitivity analysis was used to examine how each varied according to changes in the probabilities of the health scenarios. RESULTS: A total of 35 participants completed the interviews, with a median age 41 years (IQR 35-47 years). The majority of the study sample was employed (n=32, 91.4%), with a third-level (university) education (n=32, 91.4%) and with knowledge of someone with breast cancer (n=30, 85.7%). When individual preferences were accounted for, 25 (71.4%) patients preferred watchful waiting to referral for triple assessment as their preferred initial diagnostic strategy. Sensitivity analysis shows that referral for triple assessment becomes the dominant strategy at the upper probability estimate (18%) of breast cancer in the community. CONCLUSIONS: Watchful waiting is an acceptable strategy for most women who present to their general practitioner (GP) with breast symptoms. These findings suggest that current referral guidelines should take more explicit account of women's preferences in relation to their GPs initial management strategy.