A synonymous variant in GCK gene as a cause of gestational diabetes mellitus

The diagnosis of MODY as a subtype of gestational diabetes mellitus (GDM) is important for an adequate management during pregnancy and the postnatal period. The present report describes a case of GDM caused by a synonymous с.666C>G р.V222V substitution in the GCK gene. The variant, which was initially ranked as ‘likely benign’, was later proven to be pathogenic by in vitro studies. The с.666C>G substitution led to the use of a new donor splice site and synthesis of the aberrant mRNA with deletion of 16 base pairs. The case illustrates that additional clinical and experimental data may be required for the correct interpretation of sequence variants pathogenicity

Lung cancer prediction by Deep Learning to identify benign lung nodules

INTRODUCTION: Deep Learning has been proposed as promising tool to classify malignant nodules. Our aim was to retrospectively validate our Lung Cancer Prediction Convolutional Neural Network (LCP-CNN), which was trained on US screening data, on an independent dataset of indeterminate nodules in an European multicentre trial, to rule out benign nodules maintaining a high lung cancer sensitivity. METHODS: The LCP-CNN has been trained to generate a malignancy score for each nodule using CT data from the U.S. National Lung Screening Trial (NLST), and validated on CT scans containing 2106 nodules (205 lung cancers) detected in patients from from the Early Lung Cancer Diagnosis Using Artificial Intelligence and Big Data (LUCINDA) study, recruited from three tertiary referral centers in the UK, Germany and Netherlands. We pre-defined a benign nodule rule-out test, to identify benign nodules whilst maintaining a high sensitivity, by calculating thresholds on the malignancy score that achieve at least 99 % sensitivity on the NLST data. Overall performance per validation site was evaluated using Area-Under-the-ROC-Curve analysis (AUC). RESULTS: The overall AUC across the European centers was 94.5 % (95 %CI 92.6-96.1). With a high sensitivity of 99.0 %, malignancy could be ruled out in 22.1 % of the nodules, enabling 18.5 % of the patients to avoid follow-up scans. The two false-negative results both represented small typical carcinoids. CONCLUSION: The LCP-CNN, trained on participants with lung nodules from the US NLST dataset, showed excellent performance on identification of benign lung nodules in a multi-center external dataset, ruling out malignancy with high accuracy in about one fifth of the patients with 5-15 mm nodules

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma

Expression levels of mRNAs encoding for lipid sensors/transcriptional regulators in aortas from men (black bars), women (hatched bars), and in combined M+F population (grey bars).

<p>Symbol # makes a note gender difference. A, intact aortas (men, n = 15, women, n = 6); B, lesions of type I (men, n = 11, women, n = 6), C, lesions of type II (men, n = 13, women, n = 5), D, lesions of type Va (men, n = 9, women, n = 2).</p

The ratios of the contents of mRNAs encoding for lipid sensors/transcriptional regulators in pairs of injured/intact aortas from men (black bars), women (hatched bars), and in combined M+F population (grey bars).

<p>Symbol # shows significant difference from 1.0. Symbol * makes a note gender difference. A, lesion of type I/intact tissue ratios (men, n = 11, women, n = 6); B, lesion of type II/intact tissue ratios (men, n = 13, women, n = 5); C, lesion of type Va/intact tissue ratios (men, n = 9, women, n = 2).</p