Identification of Surrogate Anatomic Identifiers of Disease Progression in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in patients over 50 in the developed world. The visual impairment is due to either choroidal neovascularisation (wet AMD) or geographic atrophy (GA). Drusen is the hallmark of AMD but the presence of drusen does not inform progression to wet AMD. Although the disease is mostly bilateral, the rate of progression of disease in both eyes may not be simultaneous. If one eye is affected by wet AMD, the risk of progression of the fellow eye to wet AMD increases by 10% every year. However, there are no markers that inform the time of conversion to wet AMD. For this reason, there is an unmet need to identify biomarkers that can fully predict the progression to wet AMD in order to allow early intervention before permanent damage. My thesis aimed to assess whether changes in imaging characteristics can more precisely explain conversion. I studied various cohorts including (a) normal aging eyes (b) eyes with early/ intermediate AMD and (c) fellow eyes of unilateral wet AMD to study the conversion to wet AMD. Firstly, I evaluated longitudinally volume changes in inner and outer retinal layers of 71 eyes with early/intermediate AMD using optical coherence tomography (OCT). Our results showed that inner and outer retina layer volumes may differentiate AMD eyes from healthy eyes. When comparing those who progressed to wet AMD at year 2 to those who did not, we found that baseline volume of GCIPL may differentiate between the 2 groups. As it is an inner retinal change, I hypothesized that heritability of the retinal layers may influence the rate of retinal layer changes and that may in turn help understand the changes seen in aging and AMD. I worked with the TWIN Study database, in which OCT was done in eyes of twins of different age groups and OCT data were available on 364 eyes of 184 (92 pair) twins. I evaluated whether heritability was responsible for ageing changes of the retinal layers. I found that total retinal volume and inner retinal layer volumes may be affected by genetic factors

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer

Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations

2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)

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Multimodal imaging in the management of choroidal neovascularization secondary to central serous chorioretinopathy

The diagnosis and treatment of choroidal neovascularization (CNV) in eyes with chronic central serous chorioretinopathy (CSCR) can be challenging. The purpose of this study was to classify eyes with suspected CNV using multimodal imaging. Effect of intravitreal anti vascular endothelial growth factor (VEGF) was assessed and compared to controls. This retrospective study included chronic CSCR patients with suspected secondary CNV who received intravitreal bevacizumab. Eyes were divided into “definite CNV” and “no CNV” based on optical coherence tomography angiography (OCTA). Eyes that did not undergo OCTA imaging were considered as “Presumed CNV”. One-year outcome in visual acuity (VA) and central foveal thickness (CFT) were investigated and compared to non-treated control patients to assess the response to anti-VEGF. Logistic regression analysis was used to explore predictive biomarkers of CNV detection and improvement after anti-VEGF. Ninety-two eyes with chronic CSCR from 88 participants were included in this study. Sixty-one eyes received bevacizumab and 31 eyes were non-treated control subjects. Presence of subretinal hyperreflective material (SHRM) and shallow irregular retinal pigment epithelium (RPE) elevation (SIRE) with sub-RPE hyperreflectivity on OCT was associated with a significantly increased risk of detecting CNV on OCTA. Intravitreal anti-VEGF caused significant functional and anatomical improvement in patients with neovascular CSCR as compared to non-treated eyes. In contrast, VA and CFT changes were not significantly different between treated and non-treated CSCR with no evidence of CNV on OCTA. No clinical or anatomical biomarkers were found to be associated with response to treatment. In conclusion, OCTA should be used to confirm the presence CNV in suspected chronic CSCR patients. Intravitreal anti-VEGF treatment resulted in a significantly better 1-year outcome in patients with definitive OCTA evidence of CNV

Segmented macular layer volumes from spectral domain optical coherence tomography in 184 adult twins:Associations with age and heritability

Purpose: To investigate segmented macular layer volumes from a healthy adult twin cohort (TwinsUK), exploring changes with age and heritability. / Methods: Macular spectral domain optical coherence tomography images were acquired from monozygotic (MZ) and dizygotic (DZ) twins in a cross-sectional study. The following layer volumes were derived for circles of 3 and 6 mm diameter around the foveal center, using automated segmentation software: retinal nerve fiber layer (RNFL), ganglion cell–inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptors (PR), retinal pigment epithelium (RPE), and total retinal volume (TRV). Correlation coefficients (intereye; age; intrapair for MZ and DZ pairs) were quantified; heritability was estimated using structural equation modeling. / Results: Scans from 184 participants were included. Intereye correlation was highest for TRV and GCIPL. Negative correlations with age (for 3- or 6-mm areas, or both) were observed for TRV, RNFL, GCIPL, and INL. Positive correlations were observed for PR, RPE, and OPL. For all layers, intrapair correlation was greater for MZ than DZ pairs. Heritability estimates were highest (>80%) for TRV and GCIPL volume, and lowest for RPE volume. / Conclusions: Although TRV was negatively correlated with age, all layers did not show negative correlation. Some inner layers thinned with age, whereas some outer volumes increased (not the ONL). Reduced RPE phagocytic function with age and remodeling in the OPL could be contributing factors. Heritability estimates were highest for inner retinal layers (particularly GCIPL), and lowest for RPE volume

Map3k14 as a Regulator of Innate and Adaptive Immune Response during Acute Viral Infection

The replication of virus in secondary lymphoid organs is crucial for the activation of antigen-presenting cells. Balanced viral replication ensures the sufficient availability of antigens and production of cytokines, and both of which are needed for virus-specific immune activation and viral elimination. Host factors that regulate coordinated viral replication are not fully understood. In the study reported here, we identified Map3k14 as an important regulator of enforced viral replication in the spleen while performing genome-wide association studies of various inbred mouse lines in a model of lymphocytic choriomeningitis virus (LCMV) infection. When alymphoplasia mice (aly/aly, Map3k14aly/aly, or Nikaly/aly), which carry a mutation in Map3k14, were infected with LCMV or vesicular stomatitis virus (VSV), they display early reductions in early viral replication in the spleen, reduced innate and adaptive immune activation, and lack of viral control. Histologically, scant B cells and the lack of CD169+ macrophages correlated with reduced immune activation in Map3k14aly/aly mice. The transfer of wildtype B cells into Map3k14aly/aly mice repopulated CD169+ macrophages, restored enforced viral replication, and resulted in enhanced immune activation and faster viral control

Perfusion Imaging for Endovascular Thrombectomy in Acute Ischemic Stroke Is Associated With Improved Functional Outcomes in the Early and Late Time Windows.

BACKGROUND The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. METHODS Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (<6 hours) and late (6-24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b-3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4-6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). RESULTS We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16-1.83]; =0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; =0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage (=0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; =0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28-1.78]; =0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08-1.59]; =0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50-0.97]; =0.034; early: adjusted OR, 0.80 [95% CI, 0.65-0.99]; =0.047). CONCLUSIONS In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials