Bleeding risk evaluation in cerebral cavernous malformation, the role of medications, and hemorrhagic factors: a case-control study

Objective: Cerebral cavernous malformations (CCMs) are vascular lesions with an overall risk of rupture from 2% to 6% per year, which is associated with significant morbidity and mortality. The diagnostic incidence is increasing, so it is of paramount importance to stratify patients based on their risk of rupture. Data in the literature seem to suggest that specific medications, particularly antithrombotic and cardiovascular agents, are associated with a reduced risk of bleeding. However, the effect of the patient coagulative status on the cumulative bleeding risk remains unclear. The aim of this study was to assess the impact of different radiological, clinical, and pharmacological factors on the bleeding risk of CCMs and to assess the predictive power of an already validated scale for general bleeding risk, the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly). Method: This was a multicenter retrospective observational study. The authors collected imaging, clinical status, and therapy data on patients with bleeding and nonbleeding CCMs. Univariate analysis and subsequent multivariate logistic regression were performed between the considered variables and bleeding or nonbleeding status to identify potential independent predictors of bleeding. Results: The authors collected data on 257 patients (46.7% male, 25.3% with bleeding CCMs). Compared with patients with nonbleeding lesions, those with bleeding CCMs were younger, less frequently had hypertension, and less frequently required antiplatelet drugs and beta-blockers (all p < 0.05). Bleeding lesions, however, had significantly higher median volumes (1050 mm3 vs 523 mm3 , p < 0.001). On multivariate analyses, after adjusting for age, history of hypertension and diabetes, and use of antiplatelet drugs or beta-blockers, lesion volume ≥ 300 mm3 was the only significant predictor of bleeding (adjusted OR 3.11, 95% CI 1.09-8.86). When the diagnostic accuracy of different volume thresholds was explored, volume ≥ 300 mm3 showed a limited sensitivity (36.7%, 95% CI 24.6%-50.0%), but a high specificity 78.2% (95% CI 71.3%-84.2%), with an area under the curve of 0.57 (95% CI 0.51-0.64). Conclusions: This study supports previous findings that the CCM volume is the only factor influencing the bleeding risk. Antithrombotic agents and propranolol seem to have a protective role against the bleeding events. A high HAS-BLED score was not associated with an increased bleeding risk. Further studies are needed to confirm these results

The androgen receptor/filamin A complex as a target in prostate cancer microenvironment.

Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signalling pathways. Tumour microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumour area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. The present study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer

A comprehensive map of CNS transduction by eight recombinant adeno-associated virus serotypes upon cerebrospinal fluid administration in pigs

Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases

Comparison between intrasylvian and intracerebral hematoma associated with ruptured middle cerebral artery aneurysms: clinical implications, technical considerations, and outcome evaluation

Background: Subarachnoid hemorrhage (SAH) due to a middle cerebral artery (MCA) aneurysms rupture is often associated with intracerebral (ICH) or intrasylvian hematomas (ISH). Materials and methods: We reviewed 163 patients with ruptured MCA aneurysms associated with pure SAH or SAH+ICH/ISH. Patients were first dichotomized according to the presence of a hematoma (ICH/ISH). Then, we performed a subgroup analysis comparing ICH versus ISH in order to explore their relationship with the most relevant demographic, clinical, and angioarchitectural features. Results: Overall, 85 patients (52%) had a pure SAH, whereas 78 (48%) presented an associated ICH/ISH. No significant differences were observed in demographics and angioarchitectural features between the two groups, but Fisher grading and Hunt-Hess score were higher in patients with hematomas. A good outcome was observed in a higher percentage of patients with pure SAH compared with the others (76% Vs 44%), although mortality rates were comparable. Age, Hunt-Hess and treatment-related complications were the main outcome predictors at multivariate analysis. Patients with ICH appeared clinically worse than those with ISH. We also found that older age, higher Hunt-Hess, larger aneurysms, decompressive craniectomy and treatment-related complications were associated with poor outcome among patients with ISH, but not with ICH, which appeared per se as a more severe clinical condition. Conclusions: Our study confirm that age, Hunt-Hess and treatment-related complications influence the outcome of patients with ruptured MCA aneurysms. However, in the subgroup analysis of patients with SAH associated with ICH or ISH, only the Hunt-Hess at onset appeared as an independent predictor of outcome

Therapeutic homology-independent targeted integration in retina and liver

Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs

Preliminary surface charging analysis of Ariel payload dielectrics in early transfer orbit and L2-relevant space environment

Ariel [1] is the M4 mission of the ESA’s Cosmic Vision Program 2015-2025, whose aim is to characterize by lowresolution transit spectroscopy the atmospheres of over one thousand warm and hot exoplanets orbiting nearby stars. The operational orbit of the spacecraft is baselined as a large amplitude halo orbit around the Sun-Earth L2 Lagrangian point, as it offers the possibility of long uninterrupted observations in a fairly stable radiative and thermo-mechanical environment. A direct escape injection with a single passage through the Earth radiation belts and no eclipses is foreseen. The space environment around Earth and L2 presents significant design challenges to all spacecraft, including the effects of interactions with Sun radiation and charged particles owning to the surrounding plasma environment, potentially leading to dielectrics charging and unwanted electrostatic discharge (ESD) phenomena endangering the Payload operations and its data integrity. Here, we present some preliminary simulations and analyses about the Ariel Payload dielectrics and semiconductors charging along the transfer orbit from launch to L2 include

MicroRNA-Restricted Transgene Expression in the Retina

Background: Gene transfer using adeno-associated viral (AAV) vectors has been successfully applied in the retina for the treatment of inherited retinal dystrophies. Recently, microRNAs have been exploited to fine-tune transgene expression improving therapeutic outcomes. Here we evaluated the ability of retinal-expressed microRNAs to restrict AAV-mediated transgene expression to specific retinal cell types that represent the main targets of common inherited blinding conditions. Methodology/Principal Findings: To this end, we generated AAV2/5 vectors expressing EGFP and containing four tandem copies of miR-124 or miR-204 complementary sequences in the 39UTR of the transgene expression cassette. These vectors were administered subretinally to adult C57BL/6 mice and Large White pigs. Our results demonstrate that miR-124 and miR-204 target sequences can efficiently restrict AAV2/5-mediated transgene expression to retinal pigment epithelium and photoreceptors, respectively, in mice and pigs. Interestingly, transgene restriction was observed at low vector doses relevant to therapy. Conclusions: We conclude that microRNA-mediated regulation of transgene expression can be applied in the retina to either restrict to a specific cell type the robust expression obtained using ubiquitous promoters or to provide an additiona

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age.Methods: From the Italian LIPIGEN cohort, we selected 1188 (>= 18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation.Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives.Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age