Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.

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Cancers, Vol. 11, Pages 132: Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift

Cancers, Vol. 11, Pages 132: Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift

Cancers doi: 10.3390/cancers11020132

Authors: Pål Møller Mev Dominguez-Valentin Einar Andreas Rødland Eivind Hovig

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10–30%), compared to 35% (95% confidence interval 22–48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32–39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.

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Effects of Serum Cytochrome c on Contrast-Induced Nephropathy in Patients with ST-Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention

Background and Aims. Contrast-induced nephropathy (CIN) is a relatively infrequent complication after percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI). However, little is known about the association between cytochrome c (cyt c) and increased risk of CIN. We conducted this study to explore the impact of serum cyt c on the occurrence of CIN. Methods. We prospectively examined cyt c levels before undergoing PCI in 240 patients with STEMI. The logistic regression was performed to identify the independent risk factors for the occurrence of CIN. The receiver operating characteristic (ROC) analysis was employed to evaluate the predictive value of cyt c for the occurrence of CIN. Results. 29 patients (12.1%) had developed CIN after the PCI procedure. The cyt c levels at baseline were significantly higher in patients who developed CIN than those in non-CIN group (0.65±0.08 versus 0.58±0.1; P = 0.001). The multivariate logistic regression showed that cyt c was an independent risk factor for the occurrence of CIN (OR, 7.421; 95% CI, 6.471–20.741; P = 0.034) after adjusting for age, history of hypertension and diabetes mellitus, levels of creatinine, uric acid, and glucose. The ROC curve analysis showed that the area under the curve of cyt c was 0.697 (95% CI, 0.611–0.783; P = 0.001), and cyt c > 0.605 ng/mL predicted CIN with sensitivity of 79.3% and specificity of 56.9%. Conclusion. Our results show that a higher cyt c level was significantly associated with the occurrence of CIN after PCI in STEMI patients. This study has been registered in the Chinese Clinical Trial Registry. The clinical trial registration number is ChiCTR1800019368.

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Integrated Analysis of LncRNA-mRNA Coexpression in the Extracellular Matrix of Developing Deciduous Teeth in Miniature Pigs

Miniature pigs, a valuable alternative model for understanding human tooth development, have deciduous teeth from all four tooth families that are replaced once by permanent molars. The extracellular matrix (ECM) supports cells and maintains the integrity of tooth germs during tooth development. However, details on the role of the ECM in tooth development are poorly understood. Here, we performed long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in the ECM components of deciduous tooth germs by RNA sequencing in miniature pigs. From the early cap to the late bell stages, we identified 4,562 and 3,238 differentially expressed genes (DEGs) from E40 to E50 and E50 to E60, respectively. In addition, a total of 1,464 differentially expressed lncRNAs from E40 to E50 and 969 differentially expressed lncRNAs from E50 to E60 were obtained. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that DEGs were enriched significantly for multiple signaling pathways, especially for the ECM pathway. We then outlined the detailed dynamic gene expression profiling of ECM components during deciduous molar development. Comparison of the cap and bell stages revealed that the structure and functions of the ECM dynamically changed. The ECM-related genes, including THBS1, COL4A5, COL4A6, COL1A1, CHAD, TNR, GP1BA, and ITGA3, were significantly changed, and some were shown to enrich during the bell stage development. Finally, we outlined the coexpression of lncRNAs and ECM properties during tooth development. We showed that the interplay of key lncRNAs could change ECM processes and influence the ECM establishment of tooth patterns to accomplish full tooth formation. These results might provide information to elucidate the regulation network of the lncRNA and ECM in tooth development.

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Transient Elastography and Ultrasonography: Optimal Evaluation of Liver Fibrosis and Cirrhosis in Patients with Chronic Hepatitis B Concurrent with Nonalcoholic Fatty Liver Disease

Background and Aims. Concordance between transient elastography (TE) and ultrasonography (US) in assessing liver fibrosis in patients with chronic hepatitis B (CHB) and concurrent nonalcoholic fatty liver disease (NAFLD) has been rarely studied. This study aimed to evaluate the individual and combined performances of TE and US in assessing liver fibrosis and cirrhosis. Patients and Methods. Consecutive CHB patients with NAFLD were prospectively enrolled. TE and US examinations were performed, with liver biopsy as a reference standard. Receiver operating characteristic (ROC) curves were obtained to evaluate the diagnostic performance. Differences between the areas under the ROC curves (AUCs) were compared using DeLong's test. Results. TE and US scores correlated significantly with the histological fibrosis staging scores. TE was significantly superior to US in the diagnosis of significant fibrosis (AUC, 0.84 vs 0.73; P=0.02), advanced fibrosis (AUC, 0.95 vs 0.76; P

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Thickness and Ratio of Noncompacted and Compacted Layers of the Left Ventricular Myocardium Evaluated in 56 Normal Fetuses by Two-Dimensional Echocardiography

The thickness and ratio of noncompacted and compacted layers of the left ventricular (LV) myocardium in the normal fetus were investigated by fetal echocardiography. We aimed to investigate the compaction process of the LV myocardium during the normal gestation period and provide reference for echocardiographic diagnosis of a fetus with ventricular myocardium noncompaction. A total of 56 pregnant women in the gestational period of 23–30 weeks were included. Complete fetal echocardiography was performed with system ultrasonographic examination to exclude congenital heart malformation or extracardiac malformation. All 56 fetuses showed normal development. In the short-axis view of the fetal heart, the LV wall was divided into an upper and lower section at the level of the papillary muscle. Each section was then further divided into four segments, namely, anterior, posterior, lateral, and inferior wall. Thus, the LV wall was divided into eight segments. The thickness of the ventricular noncompacted and compacted layers and the ratio of the ventricular noncompacted to compacted layers of these segments at end-systole were measured and calculated. In echocardiography, the fetal LV myocardium is a two-layered structure: the endocardial noncompact myocardium (NC) with higher echo and the epicardium compact myocardium (C) with lower echo. The noncompacted layer is thinner than the compacted layer in the anterior wall, but thicker than the compacted layers in the posterior, lateral, and inferior wall. With respect to the upper and lower sections of the LV myocardium, the noncompacted layer in each segment of the upper section is thinner than that in each segment of the lower section, whereas the compacted layer of the upper section is thicker than that of the lower section. This study suggests that the densification of the fetal LV myocardium occurs gradually from base to apex and from the anterior to lateral, posterior, and inferior walls. This finding aids in further understanding the process of myocardial densification and provides a diagnostic reference for noncompaction of noncompaction cardiomyopathy (NCCM).

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Association between Retinal Nerve Fiber Layer Thickness and Eye Fatigue

Eye fatigue is a common health problem across all age groups. Herein, we explored the correlation between eye fatigue and thickness of the retinal nerve fiber layer (NFL). Included in the NFL are intrinsically photosensitive retinal ganglion cells (ipRGCs), which are associated with trigeminal pain. This retrospective cross-sectional study included outpatients with best-corrected visual acuity above 20/30 in both eyes and without dry eye, glaucoma, or retinal disease. A total of 1981 patients were initially enrolled and 377 patients were declared as eligible for the study analysis. We tested subjects for the presence of major ocular symptoms and measured thickness of ganglion cell complex (GCC) using optical coherence tomography. A total of 377 outpatients (46.4% men, mean age of 57.1 years) were enrolled for analysis, based on the interview-reported prevalence of six eye symptom, as follows: 31.5% for eye fatigue, 19.2% for blurring, 18.6% for dryness, 15.7% for photophobia, 13.5% for irritation, and 4.6% for pain. The macular GCC was significantly thicker in subjects with eye fatigue compared to the group not reporting eye fatigue (103.8 μm versus 100.3 μm, P = 0.014). Regression analysis identified eye fatigue (P = 0.026, β=0.122, adjusted for age and sex) and dryness (P =0.024, β=0.130) as significantly correlated with the macular GCC thickness, while the full macular thickness showed no significant correlation. In conclusions, eye fatigue and dryness were positively associated with thickness of the macular GCC. Nonvisual symptoms might therefore play a role in the development of eye fatigue.

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