Concetta Langella

Mir-23b and miR-130b expression is downregulated in pituitary adenomas.

MicroRNA (miRNA) deregulation plays a critical role in tumorigenesis. miR-23b and miR-130b are induced by thyrotropin in thyroid cells in a cAMP-dependent manner. The aim of our work has been to investigate the possible role of miR-23b and miR-130b in pituitary tumorigenesis. We have analyzed their expression in a panel of pituitary adenomas (PAs) including GH and NFPA adenomas. We report that miR-23b and miR-130b are drastically reduced in GH, gonadotroph and NFPA adenomas in comparison with normal pituitary gland. Interestingly, the overexpression of miR-23b and miR-130b inhibits cell proliferation arresting the cells in the G1 and G2 phase of the cell cycle, respectively. Moreover, we demonstrate that miR-23b and miR-130b target HMGA2 and cyclin A2 (CCNA2) genes, respectively. Finally, downregulation of miR-23b and miR-130b expression is associated with increased levels of their respective targets in human PAs. These findings suggest that miR-23b and miR-130b downregulation may contribute to pituitary tumorigenesis.

Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: Definition of clinical and molecular spectrum and identification of new diagnostic scores

Congenital Dyserythropoietic Anemia II (CDA II) is a rare hyporegenerative anemia of variable degree, whose causative gene is SEC23B. More than 60 causative mutations in 142 independent pedigrees have been described so far. However, the prevalence of the CDA II is probably underestimated, since its clinical spectrum was not yet well‐defined and thus it is often misdiagnosed with more frequent clinically‐related anemias. This study represents the first meta‐analysis on clinical and molecular spectrum of CDA II from the largest cohort of cases ever described. We characterized 41 new cases and 18 mutations not yet associated to CDA II, thus expanding the global series to 205 cases (172 unrelated) and the total number of causative variants to 84. The 68.3% of patients are included in our International Registry of CDA II (Napoli, Italy). A genotype–phenotype correlation in three genotypic groups of patients was assessed. To quantify the degree of severity in each patient, a method based on ranking score was performed. We introduced a clinical index to easily discriminate patients with a well‐compensated hemolytic anemia from those with ineffective erythropoiesis. Finally, the worldwide geographical distribution of SEC23B alleles highlighted the presence of multiple founder effects in different areas of the world. Am. J. Hematol. 89:E169–E175, 2014.

Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II

Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A-mediated which justifies these observations.

Congenital erythropoietic porphyria linked to GATA1-R216W mutation: challenges for diagnosis.

Congenital erythropoietic porphyria (CEP) is a rare genetic disease that is characterized by a severe cutaneous photosensitivity causing unrecoverable deformities, chronic hemolytic anemia requiring blood transfusion program, and by fatal systemic complications. A correct and early diagnosis is required to develop a management plan that is appropriate to the patients needs. Recently only one case of X‐linked CEP had been reported, describing the trans‐acting GATA1‐R216W mutation. Here, we have characterized two novel X‐linked CEP patients, both with misleading hematological phenotypes that include dyserythropoietic anemia, thrombocytopenia, and hereditary persistence of fetal hemoglobin. We compare the previously reported case to ours and propose a diagnostic paradigm for this variant of CEP. Finally, a correlation between phenotype variability and the presence of modifier mutations in loci related to disease‐causing gene is described.

The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias.

We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.

Successful hematopoietic stem cell transplantation in a patient with congenital dyserythropoietic anemia type II

CDA are a group of inherited, rare diseases that are characterized by dyserythropoiesis and ineffective erythropoiesis associated with transfusion dependency in approximately 10% of cases. For these latter patients, the only curative treatment is HSCT. There are very limited data on HSCT experience in this rare disease. Herein, we report a five‐yr six‐month‐old girl with compound heterozygous mutations in SEC23B gene, who was diagnosed to have CDA type II and underwent successful HSCT from her matched sibling donor.

miR-130b-3p Upregulation Contributes to the Development of Thyroid Adenomas Targeting CCDC6 Gene

We have previously studied the function of microRNAs (miRNAs) in thyroid cells using the differentiated rat thyroid PC Cl 3 cells that need thyrotropin (TSH) for their growth. The miRNA expression profile examination allowed the detection of a set of miRNAs downregulated and upregulated by TSH. Here, we first demonstrated that upregulation of miR-130b-3p occurs through a protein kinase A-cAMP-responsive element binding protein (CREB)-dependent mechanism. Then, we analyzed its expression in human thyroid follicular adenomas, where a constitutive CREB activation is frequently present. miR-130b-3p results in upregulation with a high fold-change in most thyroid follicular adenomas. Then, we identified CCDC6, coding for a protein that interacts with CREB1 leading to the transcriptional repression of CREB1 target genes, as a target of this miRNA. The targeting of CCDC6 by miR-130b-3p likely accounts for the mechanism by which its upregulation contributes to the development of thyroid adenomas increasing CREB1 activity.

Kinome expression profiling of human neuroblastoma tumors identifies potential drug targets for ultra high-risk patients

Neuroblastoma (NBL) accounts for >7% of malignancies in patients younger than 15 years. Low- and intermediate-risk patients exhibit excellent or good prognosis after treatment, whereas for high-risk (HR) patients, the estimated 5-year survival rates is still <40%. The ability to stratify HR patients that will not respond to standard treatment strategies is critical for informed treatment decisions. In this study, we have generated a specific kinome gene signature, named Kinome-27, which is able to identify a subset of HR-NBL tumors, named ultra-HR NBL, with highly aggressive clinical behavior that not adequately respond to standard treatments. We have demonstrated that NBL cell lines expressing the same kinome signature of ultra-HR tumors (ultra-HR-like cell lines) may be selectively targeted by the use of two drugs [suberoylanilide hydroxamic acid (SAHA) and Radicicol], and that the synergic combination of these drugs is able to block the ultra-HR-like cells in G2/M phase of cell cycle. The use of our signature in clinical practice will allow identifying patients with negative outcome, which would benefit from new and more personalized treatments. Preclinical in vivo studies are needed to consolidate the SAHA and Radicicol treatment in ultra-HR NBL patients.

Horst Schleusener, 1933-2015

his inaugural lecture on ‘The Regulation of TSH Synthesis and Secretion’. Together with Jürgen Quabbe and Wolfgang Oelkers, he created a competitive, academic Department of Endocrinology at Steglitz. Thyroid research gained momentum in the 1960s due to innovations in biochemistry and nuclear physics in medicine and immunology. Radioimmunoassays were introduced in thyroid testing and these allowed functional diagnostics for the first time. Schleusener’s first PubMed-listed publication with his colleague F.A. Horster described the ‘biological test for the thyrotropic hormone’ [1] , and paved the way for further research. In 1967, together with K. Schimmelpfennig and F.A. Horster, he received the first Schöller-Junkmann prize, awarded by the German Endocrine Society (DGE). This award was Horst Schleusener passed away on 12 July 2015. From the late 1960s to the 1990s of the last century, he was a leading figure in thyroidology in Germany and Europe. Born, raised and educated in Berlin, a wartime city that then got divided, he studied medicine at the Free University, from which he graduated in 1959. His academic focus on the thyroid came about by serendipity. Once asked by Werner Scherbaum why he had become a thyroidologist, he revealed that Gotthard Schettler, the head of his medical department at the time (later to become director of the Heidelberg University Hospital), advised him to choose the organ that started with an alphabetic alliteration to his surname, i.e. ‘Schilddrüse’ (thyroid). He remained faithful to this organ throughout his professional life. After his internship, he went to work for 18 months with J. Maxwell McKenzie at the Canadian McGill University of Montreal, where he further characterised the long-acting thyroid stimulator. According to his wife Annerose Schleusener, who accompanied him, this must have been one of the happiest periods of his life. After his return to Germany, he established a research group funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF) and others. In 1969, he advanced to the senior position of ‘Oberarzt’ (consultant/senior registrar), and was in the group of physicians under Max Schwab, who developed the structure of internal medicine in the Klinikum Steglitz (now known as Campus Benjamin Franklin) in Berlin. In 1971, his habilitation treatise was approved and he gave Published online: October 28, 2015