A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening

OBJECTIVE: Familial medullary thyroid carcinoma (FMTC) is caused by germ-line mutations in the RET proto-oncogene. These mutations concern mainly cysteine residues in exons 10 and 11, whereas noncysteine mutations in exons 13-16 are rare. Mutations in other exons have been reported only in isolated families. In this study we have analysed the RET gene in two FMTC families negative for mutations in the above exons. DESIGN: We have analysed exons 7-19 and 21 in one index patient from each family using DNA sequencing. PATIENTS: Twenty-eight subjects from both families were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations. RESULTS: We have found the mutation c.1597G-->T (Gly533Cys) in two Greek families with FMTC. The mutation was detected in all seven MTC patients of both families as well as in 13 asymptomatic relatives in the heterozygote state, although one of the patients was also a homozygote due to consanguinity. The mutation shows a wide clinical heterogeneity, as there are carrier patients with age of diagnosis ranging from 23 to 88 years. CONCLUSIONS: It is likely that this mutation causes FMTC, as no other mutation was found in the RET gene, the mutation co-segregates with FMTC, and family members without the mutation are clinically unaffected. As the same point mutation was previously found in a large Brazilian family, it may be present in other populations as well. Therefore, exon 8 of RET should be screened in FMTC families with no identified common RET mutations.     

Definitive-like erythroid cells derived from human embryonic stem cells coexpress high levels of embryonic and fetal globins with little or no adult globin

Human embryonic stem cells are a promising tool to study events associated with the earliest ontogenetic stages of hematopoiesis. We describe the generation of erythroid cells from hES (H1) by subsequent processing of cells present at early and late stages of embryoid body (EB) differentiation. Kinetics of hematopoietic marker emergence suggest that CD45+ hematopoiesis peaks at late D14EB differentiation stages, although low-level CD45- erythroid differentiation can be seen before that stage. By morphologic criteria, hES-derived erythroid cells were of definitive type, but these cells both at mRNA and protein levels coexpressed high levels of embryonic (epsilon) and fetal (gamma) globins, with little or no adult globin (beta). This globin expression pattern was not altered by the presence or absence of fetal bovine serum, vascular endothelial growth factor, Flt3-L, or coculture with OP-9 during erythroid differentiation and was not culture time dependent. The coexpression of both embryonic and fetal globins by definitive-type erythroid cells does not faithfully mimic either yolk sac embryonic or their fetal liver counterparts. Nevertheless, the high frequency of erythroid cells coexpressing embryonic and fetal globin generated from embryonic stem cells can serve as an invaluable tool to further explore molecular mechanisms.     

Hierarchy of molecular-pathway usage in bone marrow homing and its shift by cytokines

Efficient bone marrow (BM) homing is a prerequisite for successful engraftment of transplanted hematopoietic cells (HPCs). Contradictory conclusions about the contribution of SDF-1/CXCR4 have clouded our understanding of its role within the molecular pathway cooperation needed for BM homing, particularly with the well-defined hierarchic network of adhesion molecules. In the present study we sought to unravel cooperative and compensatory molecular pathways guiding BM homing. Fresh BM-HPCs, rendered either SDF-1 unresponsive or Gi-signaling refractory, homed quite efficiently, because of compensation by alpha4-integrin interacting with VCAM-1. The contribution of SDF-1/CXCR4- or Gi-protein-mediated signals to BM homing became apparent after their blockade was combined with deletion of alpha4-integrin, leading to dramatic reduction in BM homing. Similar conclusions were revealed when VCAM-1-deficient hosts were used. Cytokine incubation changed the functional properties of BM-HPCs and hierarchy of molecular pathway usage in homing, by shifting the dominance among the homing mediators: loss of CXCR4 or Gi-signaling now significantly reduced BM homing, with only partial compensation through alpha4/VCAM-1 and endothelial selectins. These studies depict a flexible hierarchy of cooperating homing pathways, in which dominant players are repositioned with changing cytokine milieu, and possibly source of HPCs.     

Neoadjuvant chemotherapy in breast cancer significantly reduces number of yielded lymph nodes by axillary dissection

Background

CD44 has been reported to be involved with tumor growth and metastasis and has also been implicated as a CSC marker in head and neck squamous cell cancer (HNSCC). However, the prognostic value of CD44 still remains controversial; hence, we investigated the correlation between CD44 and the clinicopathological features of HNSCC by meta-analysis.

Methods

A comprehensive search was performed using PubMed, ISI web of Science and China National Knowledge Infrastructure (CNKI) up to April 2013. Only studies with immunohistochemical staining of HNSCC were considered. Data on TNM classification, tumor grade, disease free survival and 3- or 5-year overall survival rate were extracted.

Results

Thirty studies with 2102 patients met the inclusion criteria for the meta-analysis. Fifteen studies used anti-pan-CD44 antibody, 9 used anti-CD44-v6 antibody, 2 used anti-CD44-v3 and 2 used anti-CD44s antibody, 1 used anti-CD44-v9, and 1 used anti-CD44-v6,-v3 and -v4-5 simultaneously. The total percentage of CD44 expression was 57.8%, with 49.3% in oral cancer patients, 66.4% in pharynx and 54.7% in larynx cancer patients expressing CD44. No significant correlation between clinical features and CD44 expression was revealed for oral cancer patients, but CD44 was shown to be associated with advanced T categories (larynx: RR?=?1.33, 95% CI 1.01-1.76; larynx & pharynx RR?=?1.21, 95% CI 1.08-1.35), worse N categories (larynx: RR?=?2.53, 95% CI 1.99-3.21; larynx & pharynx RR?=?1.95, 95% CI 1.35-2.82), higher tumor grades (larynx & pharynx RR?=?1.71, 95% CI 1.04-2.79) and 5-year OS rates (larynx: RR?=?0.62, 95% CI 0.47-0.83; larynx & pharynx RR?=?0.66, 95% CI 0.47-0.94) in patients with laryngeal and pharyngolaryngeal cancer. In stratified analysis, pan-CD44 and CD44-v6 expression were both correlated with 5-year OS rate of patients with laryngeal (CD44: RR?=?0.66, 95% CI 0.46-0.95; CD44-v6 RR?=?0.53, 95% CI 0.37-0.77) and pharyngolaryngeal cancer (CD44: RR?=?0.56, 95% CI 0.34-0.93; CD44-v6 RR?=?0.53, 95% CI 0.37-0.77).

Conclusions

Our analysis suggested that CD44 is related to worse T category, N category, tumor grade and prognosis, in pharyngeal and laryngeal cancer, but no clear association was revealed between CD44 expression and oral cancer.     

Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D_2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge.Changes in [¹¹C]raclopride binding potential (BP_ND) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg^?1) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D_2/3 receptor BP_ND and change in BP_ND following amphetamine as a measure of dopamine release.Voxel-based analysis revealed significantly decreased baseline [¹¹C]raclopride BP_ND in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP_ND following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP_ND changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP_ND.This study provides evidence for decreased striatal D_2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.     

Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.     

Microglial activation in healthy aging

Healthy brain aging is characterized by neuronal loss and decline of cognitive function. Neuronal loss is closely associated with microglial activation and postmortem studies have indeed suggested that activated microglia may be present in the aging brain. Microglial activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography. The purpose of this study was to measure specific binding of (R)-[(11)C]PK11195 in healthy subjects over a wide age range. Thirty-five healthy subjects (age range 19-79 years) were included. In all subjects 60-minute dynamic (R)-[(11)C]PK11195 scans were acquired. Specific binding of (R)-[(11)C]PK11195 was calculated using receptor parametric mapping in combination with supervised cluster analysis to extract the reference tissue input function. Increased binding of (R)-[(11)C]PK11195 with aging was found in frontal lobe, anterior and posterior cingulate cortex, medial inferior temporal lobe, insula, hippocampus, entorhinal cortex, thalamus, parietal and occipital lobes, and cerebellum. This indicates that activated microglia appear in several cortical and subcortical areas during healthy aging, suggesting widespread neuronal loss.     

A longitudinal, genetically informative, study of associations between anxiety sensitivity, anxiety and depression

The current study sought to examine the direction of influences on longitudinal associations between anxiety sensitivity, anxiety and depression. The continuity of genetic and environmental influences on these traits over adolescence was also investigated. Self reports of anxiety sensitivity, anxiety and depression were collected from approximately 1,300 twin and sibling pairs, on two occasions (mean ages 15 and 17). The direction and etiology of the associations between these traits were examined using longitudinal genetic cross-lagged models. All traits were stable over time and this stability accounted for the largest proportion of variance at time 2. There was, however, also evidence of reciprocal associations between variables over time. Genetic effects were fairly stable across time, although new genetic influences were evident at the second time point. Environmental effects tended to be more time specific. This study adds to our understanding of the direction of effects between anxiety sensitivity, anxiety and depression in adolescence, and the risks underlying their associations.     

A systematic evaluation and validation of subtypes of adolescent alcohol use motives: genetic and environmental contributions

Background: Alcohol use motives are closely associated with specific profiles of alcohol use and reflect a subjectively derived decisional framework based on a motivational style of responding. Adult twin studies typically estimate the heritability of alcohol use motives to be between 7 and 42%, although relatively little is known about genetic and environmental influences upon alcohol use motives in adolescence. Methods: Latent class analysis (LCA) models containing 1 through 5 classes were fitted to the data derived from 1,422 adolescent twin and siblings self‐reported alcohol use motives. Using twin models, we estimated the genetic, shared, and nonshared environmental influences to the class membership data derived from the LCA. Results: Four drinking motives classes were identified (family‐oriented, social, enhancement/social, and coping/social). The coping/social and enhancement/social classes were differentiated from the social class on measures of depression, delinquency, and aggressive behavior. Analyses indicated that nonadditive genetic factors accounted for 76% of the variance in the coping/social motives class and additive genetic influences accounted for 66% of the variance in the social motives class. There was a moderate contribution of genetic factors and shared environmental factors influencing class membership of enhancement/social motivated drinkers (28 and 20% explained variance, respectively). Substantial shared environmental influences were revealed for membership of the family‐oriented class (75%). Conclusions: Heritable influences may predispose individuals to drink to cope with negative affect, for social reasons, and to a lesser extent for enhancement. Familial environmental influences shape family‐oriented motives for drinking in adolescents.