Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15–30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10–30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10⁻⁶ and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10⁻⁴). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.     

Molecular profiling of the colon cancer in South-Eastern Romania: Results from the MERCUR study

Colorectal cancer is a heterogeneous disease with multiple epigenetic alterations and different molecular features. The molecular classification is based on 2 major distinct pathways: microsatellite stable pathway and the microsatellite instability pathway. Molecular profiling of colorectal cancer provides important information regarding treatment and prognosis. Aim of the study was to assess the frequency of microsatellite instability in colon cancer and the clinicopathological characteristics of the tumors with high level of microsatellite instability (MSI-H) in our region. The secondary outcome was to assess the frequency of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in colon cancer.The study included 129 patients with colon cancer fit for surgery. Demographic data, clinical and pathological data, immunohistochemistry staining pattern (4 mismatch repair proteins were investigated), and BRAF gene mutations were assessed. According to microsatellite instability status by polymerase chain reaction, patients were divided into 3 groups: microsatellite stable (MSS) = 108 patients, high level of microsatellite instability (MSI-H) = 15 patients and low level of microsatellite instability (MSI-L) = 6 patients. Different clinicopathological comparisons between MSS and MSI-H patients, and between MSS and MSI-L patients were performed.Microsatellite instability was found in 16.3% patients: 11.6% had MSI-H and 4.7% had MSI-L. Significantly more patients in the MSI-H group than in the MSS group were female (P = .01) and had a family history of colon cancer (P < .001). MSI-H and MSI-L groups were associated with the ascending colon location of the tumors, were mostly type G3, T2, and stage I whereas MSS tumors were mostly G2, pT3, and stage III. Overall, BRAF mutations were identified in 18/129 patients (13.9%). BRAF mutant tumors were predominantly associated with MSI-H and MSI-L tumors. Immunohistochemistry had a sensitivity of 76% and a specificity of 89% in detecting MSI tumors and an accuracy of 87.6%.The frequency of microsatellite instability in our study was 16.3%. MSI-H is a distinct molecular phenotype of colon cancer with particular features: female gender, family history of colorectal cancer, a predilection for the ascending colon, poorly differentiated, predominantly T2, and stage I. The frequency of BRAF mutations was 13.9% and mutations were more often present in the MSI tumors.     

Corticosteroids are the major contributors to the risk for serious infections in autoimmune disorders with severe renal involvement

Clinical Rheumatology - We sought to investigate the infection profile and associated risk factors in a compiled cohort of patients with autoimmune disorders with severe renal involvement treated...     

Comparative Toxicological In Vitro and In Ovo Screening of Different Orthodontic Implants Currently Used in Dentistry

Selecting the most biocompatible orthodontic implant available on the market may be a major challenge, given the wide array of orthodontic devices currently available on the market. The latest scientific data have suggested that in vitro evaluations using oral cell lines provide reliable data regarding the toxicity of residual particles released by different types of orthodontic devices. In this regard, the in vitro biocompatibility of three different commercially available implants (stainless steel and titanium-based implants) was assessed. Methods: As an in vitro model, human gingival fibroblasts (HGFs) were employed to evaluate the cellular morphology, cell viability, and cytotoxicity by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays at 24 h and 72 h post-exposure to test implants. Results: The results correlate the composition and topography of the implant surface with biological experimental evaluations related to directly affected cells (gingival fibroblasts) and toxicological results on blood vessels (hen’s egg test-chorioallantoic membrane (HET-CAM) assay). The stainless steel implant exhibits a relative cytotoxicity against HGF cells, while the other two samples induced no significant alterations of HGF cells. Conclusion: Among the three test orthodontic implants, the stainless steel implant induced slight cytotoxic effects, thus increased vigilance is required in their clinical use, especially in patients with high sensitivity to nickel.     

Palladium nanoparticles embedded in mesoporous carbons as efficient,green and reusable catalysts for mild hydrogenations of nitroarenes

The reduction of nitroarenes is the most efficient route for the preparation of aromatic primary amines. These reductions are generally performed in the presence of heterogeneous transition metal catalysts, which are rather efficient but long and tedious to prepare. In addition, they contain very expensive metals that are in most cases difficult to reuse. Therefore, the development of efficient, easily accessible and reusable Pd catalysts obtained rapidly from safe and non-toxic starting materials was implemented in this report. Two bottom-up synthesis methods were used, the first consisted in the impregnation of a micro/mesoporous carbon support with a Pd salt solution, followed by thermal reduction (at 300, 450 or 600 °C) while the second involved a direct synthesis based on the co-assembly and pyrolysis (600 °C) of a mixture of a phenolic precursor, glyoxal, a surfactant and a Pd salt. The obtained composites possess Pd nanoparticles (NPs) of tunable sizes (ranging from 1–2 to 7.0 nm) and homogeneously distributed in the carbon framework (pores/walls). It turned out that they were successfully used for mild and environment-friendly hydrogenations of nitroarenes at room temperature under H₂ (1 atm) in EtOH in the presence of only 5 mequiv. of supported Pd. The determinations of the optimal characteristics of the catalysts constituted a second objective of this study. It was found that the activity of the catalysts was strongly dependent on the Pd NPs sizes, i.e., catalysts bearing small Pd NPs (1.2 nm obtained at 300 °C and 3.4 nm obtained at 450 °C) exhibited an excellent activity, while those containing larger Pd NPs (6.4 nm and 7.0 nm obtained at 600 °C, either by indirect or direct methods) were not active. Moreover, the possibility to reuse the catalysts was shown to be dependent on the surface chemistry of the Pd NPs: the smallest Pd NPs are prone to oxidation by air and their surface was gradually covered by a PdO shell decreasing their activity during reuse. A good compromise between intrinsic catalytic activity (i.e. during first use) and possibility of reuse was found in the catalyst made by impregnation followed by reduction at 450 °C since the hydrogenation could be performed in only 2 h in EtOH or even in water. The catalyst was quantitatively recovered after reaction by filtration, used at least 7 times with no loss of efficiency. Advantageously, almost Pd-free primary aromatic amines were obtained since the Pd leaching was very low (<0.1% of the introduced amount). Compared to numerous reports from the literature, the catalysts described here were both easily accessible from eco-friendly precursors and very active for hydrogenations under mild and “green” reaction conditions.

Size induced activity and reusability of mesoporous carbons containing Pd NPs are demonstrated herein for mild and green hydrogenations of nitroarenes.     

FDG-PET SUVmax Combined with IASLC/ATS/ERS Histologic Classification Improves the Prognostic Stratification of Patients with Stage I Lung Adenocarcinoma

Background

We investigated the association between the newly proposed International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), and whether the combination of these radiologic and pathologic factors can further prognostically stratify patients with stage I lung adenocarcinoma.

Methods

We retrospectively evaluated 222 patients with pathologic stage I lung adenocarcinoma who underwent FDG-PET scanning before undergoing surgical resection between 1999 and 2005. Patients were classified by histologic grade according to the IASLC/ATS/ERS classification (low, intermediate, or high grade) and by maximum standard uptake value (SUVmax) (low?<3.0, high???3.0). The cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.

Results

Patients with high-grade histology had higher risk of recurrence (5-year CIR, 29?% [n?=?25]) than those with intermediate-grade (13?% [n?=?181]) or low-grade (11?% [n?=?16]) histology (p?=?0.046). High SUVmax was associated with high-grade histology (p?n?=?113] vs. 8?% [n?=?109]; p?=?0.013). Among patients with intermediate-grade histology, those with high SUVmax had higher risk of recurrence than those with low SUVmax (5-year CIR, 19?% [n?=?87] vs. 7?% [n?=?94]; p?=?0.033). SUVmax was associated with recurrence even after adjusting for pathologic stage (p?=?0.037).

Conclusions

SUVmax on FDG-PET correlates with the IASLC/ATS/ERS classification and can be used to stratify patients with intermediate-grade histology, the predominant histologic subtype, into two prognostic subsets.     

Apolipoprotein E polymorphism--a risk factor for metabolic syndrome.

BACKGROUND: Metabolic syndrome is closely related to several disturbances in lipid and lipoprotein metabolism. The aim of this study was to determine the association between apolipoprotein E (apoE) genotypes and the risk of metabolic syndrome and/or coronary heart disease complications. METHODS: The study included 279 subjects divided into three groups: 1) control subjects, 2) metabolic syndrome patients, and 3) obese patients with coronary heart disease. All subjects were characterized by body mass index, and plasma levels of glucose, triglycerides, cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoE genotypes were identified by PCR-restriction fragment length polymorphism using genomic DNA. RESULTS: Statistical analysis of plasma parameters showed that subjects in groups 2 and 3 had higher levels of triglycerides and lower levels of HDL-C compared to group 1. The frequencies of apoE genotypes determined in this Romanian population (65% for E3/3, 19.6% for E4/3, 9.5% for E3/2, 4.1% for E2/2, 0.6% for E4/4, 1.3% for E4/2) were in agreement with those reported for other Caucasian populations. The distribution of apoE alleles indicated a higher frequency of epsilon4 in groups 2 and 3. There was a higher frequency of the apoE4/3 genotype in groups 2 and 3, which was significantly correlated with higher levels of triglycerides and lower levels of HDL-C. CONCLUSIONS: Correlations of apoE genotypes with these markers indicate that the epsilon4 allele is an independent risk factor for metabolic syndrome.     

Development and Characterization of Fe3O4@Carbon Nanoparticles and Their Biological Screening Related to Oral Administration

The current study presents the effect of naked Fe₃O₄@Carbon nanoparticles obtained by the combustion method on primary human gingival fibroblasts (HGFs) and primary gingival keratinocytes (PGKs)—relevant cell lines of buccal oral mucosa. In this regard, the objectives of this study were as follows: (i) development via combustion method and characterization of nanosized magnetite particles with carbon on their surface, (ii) biocompatibility assessment of the obtained magnetic nanoparticles on HGF and PGK cell lines and (iii) evaluation of possible irritative reaction of Fe₃O₄@Carbon nanoparticles on the highly vascularized chorioallantoic membrane of a chick embryo. Physicochemical properties of Fe₃O₄@Carbon nanoparticles were characterized in terms of phase composition, chemical structure, and polymorphic and molecular interactions of the chemical bonds within the nanomaterial, magnetic measurements, ultrastructure, morphology, and elemental composition. The X-ray diffraction analysis revealed the formation of magnetite as phase pure without any other secondary phases, and Raman spectroscopy exhibit that the pre-formed magnetic nanoparticles were covered with carbon film, resulting from the synthesis method employed. Scanning electron microscopy shown that nanoparticles obtained were uniformly distributed, with a nearly spherical shape with sizes at the nanometric level; iron, oxygen, and carbon were the only elements detected. While biological screening of Fe₃O₄@Carbon nanoparticles revealed no significant cytotoxic potential on the HGF and PGK cell lines, a slight sign of irritation was observed on a limited area on the chorioallantoic membrane of the chick embryo.