Multi-omics analysis reveals drivers of loss of ß-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study.

AIMS: Heterogeneity in the rate of ß-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. METHODS: We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in ß-cell mass measured as fasting C-peptide. RESULTS: Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in ß-cell function. The second signature was related to translation and viral infection was inversely associated with change in ß-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid ß-cell decline. CONCLUSIONS: Features that differ between individuals with slow and rapid decline in ß-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

Coxsackievirus B Persistence Modifies the Proteome and the Secretome of Pancreatic Ductal Cells.

The group B Coxsackieviruses (CVB), belonging to the Enterovirus genus, can establish persistent infections in human cells. These persistent infections have been linked to chronic diseases including type 1 diabetes. Still, the outcomes of persistent CVB infections in human pancreas are largely unknown. We established persistent CVB infections in a human pancreatic ductal-like cell line PANC-1 using two distinct CVB1 strains and profiled infection-induced changes in cellular protein expression and secretion using mass spectrometry-based proteomics. Persistent infections, showing characteristics of carrier-state persistence, were associated with a broad spectrum of changes, including changes in mitochondrial network morphology and energy metabolism and in the regulated secretory pathway. Interestingly, the expression of antiviral immune response proteins, and also several other proteins, differed clearly between the two persistent infections. Our results provide extensive information about the protein-level changes induced by persistent CVB infection and the potential virus-associated variability in the outcomes of these infections.

Second primary cancer after major salivary gland carcinoma.

BACKGROUND: We investigated the risk of second primary cancers after major salivary gland carcinoma in Finland, with a population of 5.5 million. METHODS: Nationwide cancer registry data were used to identify patients with major salivary gland carcinoma diagnosed between 1953 and 2014. Standardized incidence ratios (SIRs) were estimated to compare their second primary cancer risk with the respective site-specific cancer risk in the general population. RESULTS: There were 1727 patients with major salivary gland carcinomas and 222 second primary cancers had been diagnosed in these patients (SIR 1.43). The risk was increased for cancers of the thyroid (SIR 5.12), breast (SIR 1.63), respiratory organs (SIR 1.63), male genital organs (SIR 1.48), melanoma of the skin (SIR 3.35), and nonmelanoma skin cancer (SIR 2.50). The risk was high during the first 5 years and after 20 years of diagnosis. CONCLUSION: Second primary cancers can occur among patients with major salivary gland carcinoma even after a long time period. This needs to be recognized in the follow-up of these patients.

Early stage minor salivary gland adenoid cystic carcinoma has favourable prognosis.

The purpose of the study was to evaluate the long-term outcome of minor salivary and mucous gland (MiSG) adenoid cystic carcinoma (ACC) of the head and neck and to compare the results with earlier reports including our recently published series on major salivary gland (MaSG) ACC. The study comprised 68 MiSG ACCs operated during 1974-2012 at the Helsinki University Hospital, Helsinki, Finland. Medical records and histological samples were reviewed. Our previously published cohort comprising 54 MaSG ACCs during the years from 1974 to 2009 was used for comparison. The most common locations were the oral cavity and sinonasal cavities. Most patients presented stages IV (33.8%) and I (23.5%) disease. Primary treatment with curative intent, mainly surgery, was offered for 64 patients. Thirty-three (51.6%) of these patients developed a disease recurrence and 22 (66.7%) patients in less than 5 years. The difference in the length of recurrence-free time (<5 vs. >5 years) had an impact on OS and DSS (p < 0.001) showing worse prognosis for the earlier recurring group. T classes 2-4 (p = 0.005, p < 0.001, and p = 0.001, respectively) and stages II-IV (p = 0.019, p < 0.001, and p = 0.002, respectively) were associated with worse OS, DSS, and DFS. MiSG ACC had a similar long-term survival compared to MaSG ACC. Patients with stage I MiSG ACC seem to carry a favourable prognosis compared with those with stages II, III, and IV tumours. It is thus noteworthy that stage II tumours represent a truly advanced disease entity warranting a more aggressive treatment approach.

Pattern of recurrent disease in major salivary gland adenocystic carcinoma.

This study aims to evaluate the long-term outcome of major salivary gland adenocystic carcinoma (ACC). This is a retrospective review of 54 cases of ACC during a 35-year period from 1974 to 2009 at the Helsinki University Central Hospital, Helsinki, Finland. Medical records and histological samples were reviewed. All patients had a minimum follow-up time of 5 years or until death. Most of the tumours occurred in the parotid gland (n = 30, 56%) followed by submandibular gland (n = 22, 41%) and sublingual gland (n = 2, 4%). Fifty-two patients (96%) were treated with curative intent. All of these patients except one were primarily treated with surgery, and 29 patients (54%) also received postoperative radiotherapy for their primary tumour. Two patients (4%) received palliative radiotherapy. For those treated with curative intent, 32 patients (62%) had disease recurrence. Twenty-four patients (75%) had their first disease recurrence within 5 years and eight patients (25%) later than 5 years. The difference in the length of recurrence-free time interval (<5 vs. >5 years) had a significant impact on 5-year overall survival (OS) and disease-specific survival (DSS). The OS, DSS and disease-free survival (DFS) across stages I-IV varied between 46-100, 50-100 and 46-100%, respectively. Age over 45 years, T stage, and presence of neck metastases had a significant negative prognostic effect. More than half of the patients had recurrent disease. An extended follow-up for these patients seems feasible as most of the distant metastases were detected within a 10-year period.