👤 Claudia Maria Radu

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM's morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin-proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM. Show less

The improper expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GIP/GIPR axis activation has been increasingly recognized in endocrine tumors, with a potential diagnostic and prognostic value. A high tumor-to-normal tissue ratio (T/N ratio) of GIPR was reported both in humans' and in rats' medullary thyroid cancer (MTC), suggesting a direct link between the neoplastic transformation and the mechanism of receptor overexpression. In this study, we evaluated the potential diagnostic and prognostic significance of GIPR expression in a large cohort of MTC patients by correlating GIPR mRNA steady-state levels to clinical phenotypes. The molecular effect of GIP/GIPR axis stimulation in MTC-derived cells was also determined. We detected GIPR expression in ~80% of tumor specimens, especially in sporadic, larger, advanced-stage cancers with higher Ki-67 values. GIPR stimulation induced cAMP elevation in MTC-derived cells and a small but significant fluctuation in Ca2+, both likely associated with increased calcitonin secretion. On the contrary, the effects on PI3K-Akt and MAPK-ERK1/2 signaling pathways were marginal. To conclude, our data confirm the high T/N GIPR ratio in MTC tumors and suggest that it may represent an index for the degree of advancement of the malignant process. We have also observed a functional coupling between GIP/GIPR axis and calcitonin secretion in MTC models. However, the molecular mechanisms underlying this process and the possible implication of GIP/GIPR axis activation in MTC diagnosis and prognosis need further evaluation. Show less

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD. Show less