Chromogranina A i jej rola w patogenezie cukrzycy

Chromogranin A is a member of the granin glycoprotein family that is expressed by the endocrine and neuroendocrine cells of different organs. Intracellularly, chromogranin A contributes to the regulation of secretion and gives several cleavage products after secretion. Some of its cleavage products modify the hormone functions in autocrine and paracrine ways, while the functions of others have not been fully understood yet. Serum chromogranin A level is most prominently used in neuroendocrine tumour diagnostics. In addition, recent studies have suggested that chromogranin A and some of its cleavage products (pancreastatin and WE-14) also play important roles in the pathogenesis of the various forms of diabetes mellitus, but their exact mechanisms still need to be clarified. Higher chromogranin A, pancreastatin, and WE-14 levels have been reported in type 1, type 2, and gestational diabetic patients compared to healthy controls. A notable connection has been inferred through the observation that type 1 diabetes mellitus is not at all or rarely developed in chromogranin A gene-knockout, non-obese diabetic model mice compared to non-knockout, non-obese diabetic mice. Pancreastatin inhibits insulin release in various cell and animal models, and WE-14 serves as an autoantigen for both CD4+ and CD8+ beta cell-destructive diabetogenic T-cell clones in type 1 diabetes. Chromogranin A contributes to the pathogenesis of diabetes mellitus according to the available literature. The current findings facilitate further investigation to unravel the deeper relationships between this glycoprotein and diabetes

Deep Learning Approaches Applied to Image Classification of Renal Tumors: A Systematic Review

Renal cancer is one of the ten most common cancers in the population that affects 65,000 new patients a year. Nowadays, to predict pathologies or classify tumors, deep learning (DL) methods are effective in addition to extracting high-performance features and dealing with segmentation tasks. This review has focused on the different studies related to the application of DL techniques for the detection or segmentation of renal tumors in patients. From the bibliographic search carried out, a total of 33 records were identified in Scopus, PubMed and Web of Science. The results derived from the systematic review give a detailed description of the research objectives, the types of images used for analysis, the data sets used, whether the database used is public or private, and the number of patients involved in the studies. The first paper where DL is applied compared to other types of tumors was in 2019 which is relatively recent. Public collection and sharing of data sets are of utmost importance to increase research in this field as many studies use private databases. We can conclude that future research will identify many benefits, such as unnecessary incisions for patients and more accurate diagnoses. As research in this field grows, the amount of open data is expected to increase.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This article is based upon work from COST Action HARMONISATION (CA20122). This research has been partially funded by the Spanish Government by the project PID2021-127275OB-I00, FEDER “Una manera de hacer Europa”

Heterogeneous genetic background of Hungarian patients with pheochromocytoma/paraganglioma requires gene panel testing

Introduction Pheochromocytomas and paragangliomas (Pheo/PGL) are rare neuroendocrine tumours arising from the adrenal medulla or the symphathetic paraganglia, respectively. Germline mutations are present in w40% of the patients. To date, at least 16 genes have been demonstrated to be involved in the genetic background of Pheo/PGL. Prioritization in order of genes tested can be applied, but if the probability of a disease-associated germline mutation exceeds 10% the testing of all susceptibility genes is recommended. Using next generation sequencing (NGS) based methods for genetic testing of Pheo/PGL associated genes progressively becomes part of the routine diagnostics. Objective To assess the genetic background of Hungarian patients with Pheo/PGL and to develop a NGS based gene panel assay for analysis of Pheo/PGL susceptibility genes. Methods We examined 131 patients with the diagnosis of Pheo/PGL diagnosed and nursed at the 2nd Department of Medicine, Semmelweis University. The prevalence of the germline mutations of Pheo/PGL genes was determined using conventional methods. Genotype-phenotype correlations were evaluated. A gene panel covering 15 genes (RET, VHL, NF1, EPAS, EGLN1, KIF1B, SDHA, SDHB, SDHAF2, SDHC, SDHD, FH, MAX, TMEM127, MEN1) was developed and analytical sensitivity was evaluated on 36 patients with known genetic background. Library preparation was performed using SeqCapEZ capture platform with our probe design. Illumina MiSeq instrument was used for sequencing. Sequencing data were analysed with GATK workflow. Variant annotation was performed with SNPeffect. Results Germline mutations of Pheo/PGL genes were present in at 34% of the patients: 10 (7.6%) SDHB, 9 (6.9%) RET, 5 (3.8%) VHL, TMEM127, MDH2, 4 (3%) NF1, 3 (2.3%) SDHD, 2 (1.5%) SDHC and KIF1B. 5 of 10 SDHB mutation carriers developed malignant disease. Homozygous form of a MDH2 variant was associated with malignancy. Among the 10 patients with bilateral adrenal Pheo 4 RET, 2 TMEM127 and 1 VHL mutations were identified. The coverage of genes in our panel was higher than 150 reads in all regions and all known mutations were correctly identified. Discussion Our findings regarding the prevalence of germline mutations in the development of Pheo/PGL are in accordance with the literature. No founder mutation occurred in our population as we could detect mutations in 9 genes, underlining the need of novel methods for mutation analysis in everyday clinical practice. Our NGSbased gene panel performed accurately, however two recently identified genes (MDH2, GOT2) were not covered

Next generation sequencing for characterization of mitochondrial genome in pituitary adenomas

Introduction Disrupted mitochondrial functions and genetic variations of mitochondrial DNA (mtDNA) have been observed in different tumors. Regarding pituitary adenomas mtDNA was evaluated only in oncocytic type using PCR based methods and it showed high prevalence of Complex I variants. Next generation sequencing (NGS) allows high throughput sequencing and it is useful for accurate identification of heteroplasmy of mitochondrial genome as well. Aim We aimed to investigate the entire mitochondrial genome in different adenoma types. Material and methods We collected 22 gonadotroph (GO), 11 growth hormone producing (GH) and 11 null-cell (NC) adenoma specimens from samples removed by transsphenoidal surgery. From fresh frozen tissues DNA extraction was performed using QIAamp Fast DNA Tissue Kit. For library preparation VariantPro™ Amplicon Mitochondrion Panel kit was used. The total mtDNA (16569 bp) was sequenced on Illumina MiSeq Instrument. Following complex bioinformatic analysis Revised Cambridge Reference Sequence (rCRS) of the human mitochondrial DNA was used as reference. Heteroplasmy was determined using 3% cutoff. Results. The whole mitochondrial genome were covered by 630±370 (avg±SE) reads per base. 496 variants were identified in adenomas compared to reference sequence. Overall a low (7.22%) heteroplasmy prevalence was found. Based on mitochondrial sequence variants by hierarchical cluster analysis we could not discriminate different adenoma types. No association between Ki-67 index or recurrent-nonrecurrent status of adenomas and mitochondrial variants were detected. Four variants appeared more often in null-cell adenomas compared to gonadotroph adenomas (chrM_188: 18% vs. 0%, chrM_16093: 18% vs. 0%, chrM_185: 27% vs. 0% and chrM_14798: 36% vs. 5%; Padj=0.0246, 0.0246, 0.01542 and 0.01829, respectively). Of these variants chrM_14798, chrM_4216 and chrM_15452 are non-synonymous polymorphisms leading to amino acid change in MT-CYB (mitochondrially encoded cytochrome b) and in MT-ND1 (mitochondrially encoded NADH dehydrogenase 1) genes. We identified chrM_16189 variant (non-protein coding variant) in 40% (6/15) of nonrecurrent adenomas compared to recurrent ones where this variant was not present (0/11) (p=0.0209). Conclusions Next-generation sequencing is a reliable method for investigating mitochondrial genome and heteroplasmy in pituitary adenomas. In pituitary adenomas the prevalence of heteroplasmy of mitochondrial genome is low suggesting that these alterations may not influence mitochondrial function considerably. Of pituitary tumours only null cell adenomas possess alterations of mitochondrial genome with potential functional consequences suggesting that during the development of this subtype of pituitary tumours mitochondrial function-associated mechanisms may have role

A SHOX géndeletio előfordulása idiopathiás alacsonynövésben

INTRODUCTION: The isolated haploinsufficiency of the SHOX gene is one of the most common cause of short stature determined by monogenic mutations. The heterozygous deviation of the gene can be detected in 2-15% of patients with idiopathic short stature (ISS), in 50-90% of patients with Leri-Weill dyschondrosteosis syndrome (LWS), and in almost 100% of patients with Turner syndrome. AIM: The aim of our study was to evaluate the frequency of SHOX gene haploinsufficiency in children with ISS, LWS and in patients having Turner syndrome phenotype (TF), but normal karyotype, and to identify the dysmorphic signs characteristic for SHOX gene deficiency. METHOD: A total of 144 patients were included in the study. Multiplex Ligation-dependent Probe Amplification (MLPA) method was used to identify the SHOX gene haploinsufficiency. The relationships between clinical data (axiological parameters, skeletal disorders, dysmorphic signs) and genotype were analyzed by statistical methods. RESULTS: 11 (7.6%) of the 144 patients showed SHOX gene deficiency with female dominance (8/11, 81% female). The SHOX positive patients had a significantly higher BMI (in 5/11 vs. 20/133 cases, p<0.02) and presented more frequent dysmorphic signs (9/11vs 62/133, p = 0.02). Madelung deformity of the upper limbs was also significantly more frequent among the SHOX positive patients (4/11, i.e. 36%, vs. 14/133, i.e. 10%, p = 0.0066). There were no statistically significant differences between the mean age, mean height and auxological measurements (sitting height/height, arm span/height) between the two groups of patients. CONCLUSIONS: The occurrence of SHOX gene haploinsufficiency observed in our population corresponds to the literature data. In SHOX positive patients, in addition to short stature, the dysmorphic signs have a positive predictive value for SHOX gene alterations. However, the SHOX deletion detected in a patient with idiopathic short stature without dysmorphic signs suggest that SHOX deletion analysis can be recommended in patients with ISS. Orv Hetil. 2017; 158(34): 1351-1356

Head and neck paragangliomas: clinical and molecular genetic classification

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I–III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies

Deep Learning Approaches Applied to Image Classification of Renal Tumors: A Systematic Review

Renal cancer is one of the ten most common cancers in the population that affects 65,000 new patients a year. Nowadays, to predict pathologies or classify tumors, deep learning (DL) methods are effective in addition to extracting high-performance features and dealing with segmentation tasks. This review has focused on the different studies related to the application of DL techniques for the detection or segmentation of renal tumors in patients. From the bibliographic search carried out, a total of 33 records were identified in Scopus, PubMed and Web of Science. The results derived from the systematic review give a detailed description of the research objectives, the types of images used for analysis, the data sets used, whether the database used is public or private, and the number of patients involved in the studies. The first paper where DL is applied compared to other types of tumors was in 2019 which is relatively recent. Public collection and sharing of data sets are of utmost importance to increase research in this field as many studies use private databases. We can conclude that future research will identify many benefits, such as unnecessary incisions for patients and more accurate diagnoses. As research in this field grows, the amount of open data is expected to increase

Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by development of cystic and tumorous lesions at multiple sites, including the brain, spinal cord, kidneys, adrenals, pancreas, epididymis and eyes. The clinical phenotype results from molecular abnormalities of the VHL tumor suppressor gene, mapped to human chromosome 3p25-26. The VHL gene encodes two functionally active VHL proteins due to the presence of two translational initiation sites separated by 53 codons. The majority of disease-causing mutations have been detected downstream of the second translational initiation site, but there are conflicting data as to whether few mutations located in the first 53 codons, such as the Pro25Leu could have a pathogenic role. In this paper we report a large Hungarian VHL type 2 family consisting of 32 members in whom a disease-causing AGT80AAT (Ser80Ile) c.239G>A, p.Ser80Ile mutation, but not the concurrent CCT25CTT (Pro25Leu) c.74C>T, p.Pro25Leu variant co-segregated with the disease. To our knowledge, the Ser80Ile mutation has not been previously described in VHL type 2 patients with high risk of pheochromocytoma and renal cell cancer. Therefore, this finding represents a novel genotype-phenotype association and VHL kindreds with Ser80Ile mutation will require careful surveillance for pheochromocytoma. We concluded that the Pro25Leu variant is a rare, neutral variant, but the presence such a rare gene variant may make genetic counseling difficult