Souzan Salemi

New N-terminal located mutation (Q4ter) within the POU1F1-gene (PIT-1) causes recessive combined pituitary hormone deficiency and variable phenotype.

OBJECTIVE Growth is an inherent property of life. About 10% of the congenital forms of growth retardation and short stature are genetically caused. Beside the gene involved in direct GH-production, there are different candidate genes important for appropriate pituitary development causing combined pituitary hormone deficiency (CPHD). However, severe growth retardation and failure to thrive remain the leading reason for medical assessment in these patients. PATIENTS AND METHODS We report two siblings of a healthy but consanguineous Malaysian family presenting with severe short stature caused by CPHD with a variable phenotype. Importantly, at the beginning the girl presented with isolated GHD, whereas the boy was hypothyroid. As the most common gene alterations responsible for CPHD are within either the PROP-1- or the POU1F1- (PIT-1)-gene these two genes were further studied. RESULTS Subsequent sequencing of the six exons of the POU1F1-gene allowed the identification of a new N-terminal mutation (Q4ter) in these two children. A substitution of C to T induced a change from a glutamine (CAA) to a stop codon (TAA) in exon 1 of the PIT-1 protein. Both affected children were homozygous for the mutation, whereas the mother and father were heterozygous. CONCLUSION We describe two children with autosomal recessive inherited CPHD caused by a new N-terminal located mutation within the PUO1F1-gene. The clinical history of these two children underline the phenotypic variability and support the fact that children with any isolated and/or combined PHD need to be closely followed as at an any time other hormonal deficiencies may occur. In addition, molecular analysis of the possible genes involved might be most helpful for the future follow-up.

Human adipose-derived mesenchymal stromal cells may promote breast cancer progression and metastatic spread

Background: Stem cell–enriched fat grafting has been proposed as a potential therapy for reconstructive, restorative, or enhancement-related procedures of the breast. Its role in postoncologic breast reconstruction is still emerging, with concerns about safety. The authors investigated the dose-dependent interaction between human adipose-derived mesenchymal stromal cells (AD-MSCs) and human breast cancer cell (BCC) lines [MDA-MB-231 (MDA) and MCF-7 (MCF)] focusing on tumor microenvironment, tumor growth, and metastatic spread. Methods: Adipose-derived mesenchymal stromal cell influence on viability and factor expression [regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-&agr;, and eotaxin) of breast cancer cells was studied in vitro using direct and indirect co-culture systems. Groups were formed according to adipose-derived mesenchymal stromal cell–to–cancer cell number ratio [MDA/MCF only, AD-MSClow/(MDA/MCF), and AD-MSChigh/(MDA/MCF)]. A humanized orthotopic murine cancer model was used to evaluate breast cancer progression and metastasis (n = 10/group). Cells were injected into the mammary pad in different ratios and animals were monitored over 42 days. Microdialysis was performed to analyze RANTES levels in the tumor microenvironment (days 21 and 42). Primary and metastatic tumors were weighed and analyzed for oncogene, growth factor, and metastatic marker expression. Results: MDA cell viability increased from 45.5 percent to 95.5 percent in presence of adipose-derived mesenchymal stromal cells in vitro. In vivo, animals with AD-MSChigh showed increased mean tumor weight (MDA, p < 0.01; MCF versus controls, p < 0.05) and metastatic occurrence (40 percent in MDA; 30 percent in MCF versus 0 percent in controls). Cytokine analysis revealed switching of MCF tumor phenotype to a more malignant type in the presence of adipose-derived mesenchymal stromal cells. Conclusion: Human adipose-derived mesenchymal stromal cells may promote progression and metastatic spread in breast cancer through a switch to a more malignant phenotype with worse prognosis.

A novel FIP1L1‐PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

Background:  The Fip1‐like‐1–platelet‐derived growth factor receptor alpha (FIP1L1‐PDGFRA) gene fusion is a common cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), and patients suffering from this particular subgroup of CEL/HES respond to low‐dose imatinib therapy. However, some patients may develop imatinib resistance because of an acquired T674I mutation, which is believed to prevent drug binding through steric hindrance.

Use of the Short-Form-36 Health Survey to detect a subgroup of fibromyalgia patients with psychological dysfunction

The aim of the present study was to examine the in-depth application of the Short-Form-(SF)-36 Health Survey to score the general well-being in fibromyalgia syndrome (FS) patients. Quality of life was evaluated in 12 patients with FS. With respect to mental well-being (social functioning, role limitation due to emotional health problems, and mental health), two distinguished groups were found concerning psychological functioning. One group (n = 8) demonstrated psychological dysfunction, whereas the other (n = 4) showed normal psychological scores. Physical well-being scores (physical functioning, role limitation due to physical health problems, bodily pain, general health, and vitality) did not differ between FS patients but were altogether below the normal range. Regarding the psychological scores of the two groups of patients, SF-36 can be used to differentiate between patients with and without psychological dysfunction independent of pain. Therefore, we propose that the SF-36 could be of help to provide the most adequate therapy to achieve an optimal outcome in patients with FS and psychological disturbances.

TRAIL mediated signaling in human mast cells: the influence of IgE-dependent activation.

Background:  Mast cells activation through FcɛRI cross‐linking has a pivotal role in the initiation of allergic reactions. The influence of this activation on programmed cell death of human mast cells has not yet been clarified. This study evaluates the influence of IgE‐dependent activation alone and in synergy with TRAIL on the expression of molecules involved in the apoptotic signal transduction.

Human mast cells express intracellular TRAIL

Recently we demonstrated that human mast cells (MC) express functional TRAIL death receptors. Here we assessed the expression of TRAIL on both mRNA and protein level in cord blood derived MC (CBMC) and HMC-1. The TRAIL release either spontaneous or induced by LPS, IFN-gamma and IgE-dependent activation, was evaluated as well. The protein location was restricted to the intracellular compartment in CBMC, but not in HMC-1. The intracellular TRAIL was not localized inside the granules. The treatment with IFN-gamma and LPS up-regulated intracellular TRAIL expression in CBMC, but did not induce its release. These in vitro data show that human MC can produce and express intracellular TRAIL whose location could not be altered by different stimuli.

Leydig-cell tumour in children: variable clinical presentation, diagnostic features, follow-up and genetic analysis of four cases.

Background: Testicular tumours are relatively uncommon in infants and children, accounting for only 1–2 % of all paediatric solid tumours. Of these approximately 1.5% are Leydig-cell tumours. Further, activating mutations of the luteinizing hormone receptor gene (LHR), as well as of the G protein genes, such as Gsalpha (gsp) and Gialpha (gip2) subunits, and cyclin-dependent kinase gene 4(CDK4) have been associated with the development of several endocrine neoplasms. Aims/Methods: In this report, the clinical variability of Leydig-cell tumours in four children is described. The LHR-, gsp-, gip2- and CDK4 genes were investigated to establish the possible molecular pathogenesis of the variable phenotype of the Leydig-cell tumours. Results: No activating mutations in these genes were found in the four Leydig-cell tumours studied. Therefore, the absence of activating mutations in LHR, as well as in both the ‘hot spot’ regions for activating mutations within the G-alpha subunits and in the regulatory ‘hot spot’ on the CDK4 genes in these tumours indicates molecular heterogeneity among Leydig-cell tumours. Conclusion: Four children with a variable phenotype caused by Leydig-cell tumours are described. A molecular analysis of all the ‘activating’ genes and mutational regions known so far was performed, but no abnormalities were found. The lessons learnt from these clinically variable cases are: perform ultrasound early and most importantly, consider discrepancies between testicular swelling, tumour size and androgen production.

Original article: TRAIL mediated signaling in human mast cells: the influence of IgE-dependent activation

Background:  Mast cells activation through FcɛRI cross‐linking has a pivotal role in the initiation of allergic reactions. The influence of this activation on programmed cell death of human mast cells has not yet been clarified. This study evaluates the influence of IgE‐dependent activation alone and in synergy with TRAIL on the expression of molecules involved in the apoptotic signal transduction.

The combination of electric current and copper promotes neuronal differentiation of adipose-derived stem cells.

Damage to the nervous system can be caused by several types of insults, and it always has a great effect on the life of an individual. Due to the limited availability of neural transplants, alternative approaches for neural regeneration must be developed. Stem cells have a great potential to support neuronal regeneration. Human adipose-derived stem cells (hADSCs) have gained increasing interest in the fields of regenerative medicine due to their multilineage potential and easy harvest compared to other stem cells. In this study, we present a growth factor-free method for the differentiation of hADSCs toward neuron-like cells. We investigated the effect of electric current and copper on neuronal differentiation. We analyzed the morphological changes, the mRNA and protein expression levels in the stimulated cells and showed that the combination of current and copper induces stem cell differentiation toward the neuronal lineage with elongation of the cells and the upregulation of neuron-specific genes and proteins. The induction of the neuronal differentiation of hADSCs by electric field and copper may offer a novel approach for stem cell differentiation and may be a useful tool for safe stem cell-based therapeutic applications.

Autosomal-dominant isolated growth hormone deficiency (IGHD type II) with normal GH-1 gene.

Background: Autosomal-dominant isolated GH deficiency (IGHD) is a rare disorder that is commonly believed to be due to heterozygous mutations in the GH-1 gene (GH-1). These mutations cause the production of a protein that affects the release of the product of the normal allele. Rarely, heterozygous mutations in the gene encoding for HESX-1 gene (HESX-1) may cause autosomal-dominant IGHD, with penetrance that has been shown to be variable in both humans and mice. Subjects and Methods: We have sequenced the whole GH-1 in the index cases of 30 families with autosomal-dominant IGHD. In all the families other possible causes of GH deficiency and other pituitary hormones deficits were excluded. We here describe the clinical, biochemical and radiological picture of the families without GH-1 mutations. In these families, we also sequenced the HESX-1. Results: The index cases of the five families with autosomal-dominant IGHD had normal GH-1, including the intronic sequences. They had no HESX-1 mutations. Conclusion: This study shows that GH-1 mutations are absent in 5/30 (16.6%) of the families with autosomal-dominant IGHD and raises the possibility that mutations in other gene(s) may be involved in IGHD with this mode of transmission.