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Objectives Hereditary xanthinuria is a rare, autosomal and recessive disorder characterized by severe hypouricemia and increased xanthine excretion, caused by a deficiency of xanthine dehydrogenase/oxidase (XDH/XO, EC: 1.17.1.4/1.17.3.2) in type I, or by a deficiency of XDH/XO and aldehyde oxidase (AOX, EC: 1.2.3.1) in type II. Methods We describe a novel point mutation in the XDH gene in homozygosis found in a patient with very low serum and urine levels of uric acid, together with xanthinuria. He was asymptomatic but renal calculi were discovered during imaging. Results Additional cases were found in his family and dietary recommendations were made in order to prevent further complications. Conclusions Hereditary xanthinuria is an underdiagnosed pathology, often found in a routine analysis that shows hypouricemia. It is important for Laboratory Medicine to acknowledge how to guide clinicians in the diagnosis.

Background: Oral leukoplakia is one of the most common oral premalignant disorder. The classical evaluation through tissue biopsy is not always valid to evaluate the risk of malignization. Material and methods: RT-qPCR was performed on 47 blood samples (21 patients with leukoplakia, 2 with oral squamous cell carcinoma (OSCC), and 24 healthy patients) and on 11 tissue samples (3 leukoplakia, 4 OSCC, and 4 samples of healthy tissue). Results: There are significant differences in expression between the different groups (F = 4.057, p = .006). The Duncan post hoc test shows that the only group that differentiates is the tumour tissue. Using Wilcoxon test, different covariables of patients with leukoplakia were analysed with respect to the group of healthy patients and no significant differences were observed. Conclusions: The diagnostic route through liquid biopsy has not been conclusive in this study, but there are significant differences in the levels analysed in the different tissue samples.

Reduced genetic variability in isolated populations promotes the prevalence of long contiguous stretches of homozygosity (LCSH) that may carry deleterious mutations, manifesting recessive syndromes such as Alstrom syndrome (OMIM # 203800), caused principally by mutations in exons 8, 10, and 16 and deletions/insertions along the ALMS1 gene. Here, Sanger sequencing of these exons and whole-genome copy-number variants/single-nucleotide polymorphisms (SNPs) microarray were used to characterize ALMS1 gene in a 19-year-old Pakistani female with Alstrom syndrome. Sequencing did not reveal pathogenic alterations but described a set of homozygous polymorphisms. The microarray revealed these SNPs were included in an 8.24 Mb LCSH in 2p12.2p13 that contained a homozygous deletion including exons 13-16 of ALMS1 gene. Therefore, reduced genetic variability in Pakistani population enhanced the inheritance of the homozygous deletion causing Alstrom syndrome. The comparison of the deletion with known deletions spanning exons 13-16, described on Middle Eastern patients, suggested a fixation of the deletion in a specific haplotype.

Introduction. Slow-channel congenital myasthenic syndrome is an autosomal dominant inherited progressive neuromuscular disorder caused by abnormal gating of mutant acetylcholine receptors in the neuromuscular junction. Its pathological hallmark is selective degeneration of the endplate and postsynaptic membrane due to calcium overload. Pyridostigmine should be avoided in this syndrome, being quinidine or fluoxetine the current recommended therapies. Case report. An 11-year-old girl with a limb-girdle phenotype of slow-channel congenital myasthenic syndrome presenting with a slowly progressive fatigable weakness at the age of 8 years. After a clinical worsening with pyridostigmine, empirically started before the exome sequencing results were available, a dramatic and sustained response to ephedrine monotherapy was observed. Whole exome sequencing revealed a de novo heterozygous mutation in CHRNB1 gene: c.865G>A; p.Val289Met (NM_000747.2). An abnormal decrement in amplitude (23.9%) from the first to fifth intravollley waveform was revealed after repetitive peroneal nerve stimulation at low frequencies. In addition, a second smaller compound muscle action potential after the peak of the main M-wave in median, ulnar and peroneal motor nerves was observed. Conclusion. Favorable responses to adrenergic agonists added to fluoxetine had been reported. However, to the best of our knowledge this is the first report on effective monotherapy with ephedrine in a slow-channel congenital myasthenic syndrome patient. Adrenergic agonists may be considered as a therapeutic option in patients with this syndrome.

We described earlier the possible role of ATPaseC1 expression as a diagnostic and prognostic marker for oral cancer; others have reported its use for tumors of the lung and breast. We assessed ATPaseC1 expression in a sample of oral squamous cell carcinoma (OSCC) using tissue microarrays (TMAs) to analyze the relation between ATPaseC1 expression and clinical, histopathological and prognostic parameters. We performed a retrospective study of 48 cases of OSCC. We constructed TMAs using two different regions of each tumor. V-ATPaseC1 immunohistochemistry was performed and assessed semiquantitatively. ATPaseC1 staining was observed in most of the neoplastic cells in all tumors. Staining was diffusely cytoplasmic and, to a lesser extent, nuclear. The degree of concordance between the measurements performed in tissue microarray 1 (TMA1) and tissue microarray 2 (TMA2), as evaluated using the intra-class correlation coefficient (ICC), was low. We found great variability in the immunohistochemical staining of the different regions of each tumor. We found 16 cases with mild expression (33.3%), 20 with moderate expression (41.7%) and 12 with intense expression (25%). Differences in the clinical-pathological variables studied were not statistically significant. The difficulty of immunohistochemical evaluation, the heterogeneity of the carcinomas and the fact that evaluation of expression requires semiquantitative analysis render the reliability of the results obtained from TMA-based techniques questionable.

Monocarboxylate transporter 8 (MCT8) is an active and specific thyroid hormone transporter into neurons. MCT8 mutations cause an X-linked condition known as Allan-Herndon-Dudley syndrome and are characterized by impaired psychomotor development and typical abnormal thyroid function. We describe a 10-year-old boy with severe cognitive disability, axial hypotonia, spastic quadriplegia and sporadic dyskinetic episodes. He initially presented with thyroid dysfunction (high FT3, low rT3, low FT4 and normal TSH) and generalized retardation of the cerebral and cerebellar myelination in brain magnetic resonance imaging. The clinical and laboratory findings led to sequencing of the SLC16A2/MCT8 gene, which identified a novel missense mutation in exon 5. The study of peripheral markers of thyroid function suggests a paradoxical state of thyrotoxicosis in some peripheral tissues. Our patient had a typical clinical presentation at birth but because of the rarity of his disease his diagnosis was not made until the age of 7. The delay can also be explained by the omission of the free T3 assay in the first thyroid evaluation performed. This case therefore highlights the possible benefit of including the T3 assay in the study of patients with severe psychomotor disability of unknown etiology, thus eliminating extra costs for unnecessary complementary diagnostic tests.

The presence and degree of dysplasia are important diagnostic and prognostic criteria for oral leukoplakia, but evaluation of dysplasia is difficult and subjective. Carbonic anhydrase-IX (CA-IX) is expressed primarily in tumor cells and is considered a specific hypoxia marker. We investigated the role of CA-IX in oral leukoplakia. We investigated 30 specimens of oral leukoplakia and 35 dysplasia specimens adjacent to the tumor margin. We analyzed clinical variables including age, sex, degree of dysplasia, and smoking, clinical appearance of leukoplakia, number of lesions, location, size, clinical monitoring, malignant transformation and recurrence. For the immunohistochemical study, we used a noncommercial monoclonal antibody against human CA-IX MAb M75. We found greater CA-IX positivity in nonsmokers, erythroplakia and mottled leukoplakia, those located on the tongue, patients with multiple lesions, 2-4 cm leukoplakias and in recurrent cases, although differences were not statistically significant. All lesions in all samples without dysplasia were negative for CA-IX; however, for all other categories of dysplasia, the percentages of positivity and negativity varied. Regarding the diagnostic index values, we found a sensitivity of 32%, specificity of 100%, a positive predictive value of 100% and a negative predictive value of 13%. Leukoplakias appear mainly in females and potentially are malignant; more than 90% have some degree of dysplasia, and therefore require close clinical and histopathological monitoring. The CA-IX immunohistochemical marker may be useful for screening samples without dysplasia owing to its high specificity.

INTRODUCTION: The aetiology of autosomal dominant mental retardation type 1, also known as pseudo-Angelman, MBD5-associated neurodevelopmental disorder or MBD5 haploinsufficiency, lies in a microdeletion of chromosome 2q23.1 or in a specific alteration of the MBD5 gene, which constitutes the minimum region affected in the aforementioned microdeletion. AIM: To report the case of a girl with a heterozygous de novo mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria. CASE REPORT: We report the case of an 8-year-old girl who was submitted to a developmental follow-up from the age of 18 months after presenting the association of severe intellectual disability and motor delay, lack of language development, segmental hypotonia, a wide forehead and kyphoscoliosis. Magnetic resonance imaging of the brain revealed the presence of a bilateral band heterotopia and parietooccipital polymicrogiria predominant on the left side. In the exome the de novo heterozygous variant c.397+1G>C was detected in the MBD5 gene. CONCLUSION: This is the first observation of a heterozygous mutation in the MBD5 gene associated with a neuronal migration disorder.

Carbonic anhydrase (CA) IX is a hypoxia marker located almost exclusively in tumor cells. We analyzed the expression of this marker in dysplastic lesions adjacent to the surgical resection margin in patients with oral squamous cell carcinoma. We investigated 70 archived tumors, 36 of which showed dysplasia adjacent to the surgical margin. We used tissue microarray technology to perform an immunohistochemical study of CA IX expression. We found 12 (33.3%) cases of mild dysplasia (10 negative, 2 positive for CA IX), five (13.9%) cases of moderate dysplasia (3 negative, 2 positive for CA IX), 1 (2.8%) case of severe dysplasia (negative for CA IX) and 18 (50%) cases of carcinoma in situ (10 negative, 8 positive for CA IX). In cases of intense expression of CA IX in the tumor, the same distribution of positive and negative cases was observed in all degrees of dysplasia (mild, moderate, severe), although cases of carcinoma in situ tended to be CA IX positive.

Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4 Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926–36576388) x1 dn in a child with 3 years and 4 months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80 kb of exon 1 of BDNF . The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor ( BDNF ) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the haploinsufficiency of the BDNF gene could constitute an adequate model to study in depth their effects.

J Oral Pathol Med (2012) Introduction: Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues. Material and methods: This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves. Results: Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III–IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I-II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank = 6.1, P value = 0.0484. Conclusions: Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor.

Tumoral microenvironments play a key role in the evolution of solid tumors. Tumor hypoxia is actively involved in the promotion of genetic instability, the invasive capacity of tumor cells, metastasis, and a worsening of the clinical evolution. Endogenous hypoxia markers are controlled by hypoxia-related genes, formed by HIF-1, which is related to several target genes that involve the energy metabolism, angiogenesis, and transmembrane carbonic anhydrases (CAs), mainly CA-IX that is one of the tumor-related carbonic anhydrases. The goal of this paper is to establish the role of CA-IX as a hypoxia marker in OSCC, while analyzing its expression in this type of tumors and its relationship with several clinical and pathological parameters and prognosis, evaluating its relationship with angiogenesis, other hypoxia markers, and clarifying its role in chemotherapy and radiotherapy resistance.

J Oral Pathol Med (2012) 41: 433–443 A micro RNA (miRNA) is a single-stranded endogenous, non-coding RNA, with length ranging between 18 and 24 nucleotides and the ability of regulating the expression of other genes on a post-transcriptional level by means of various processes, degradation or repression of target mRNA. miRNAs play a crucial role in regulating fundamental processes such as cell cycle, differentiation and apoptosis; thus, their deregulation can affect normal cell growth and development, and even participate in carcinogenesis. The goals of this paper are: to outline the formation and functions of miRNAs; to determine their role in oral squamous cell carcinoma; to analyze the different miRNAs described and their roles as oncogenes or tumor suppressor genes, depending on their overexpression or subexpression; to describe the different polymorphisms and epigenetic alterations identified; and to determine their role in multidrug resistance.

The β2-adrenergic receptor is most frequently involved in carcinogenic processes. Earlier studies have established a relation between the β2-adrenergic receptor and various characteristics of cancer including cell proliferation, apoptosis, chemotaxis, metastasis, tumor growth and angiogenesis. Our goal was to determine differential expression of the genes involved in adrenergic receptors using DNA microarrays and to confirm their under- or overexpression using real-time quantitative PCR. Five of the nine genes investigated showed significantly altered expression levels in tumor cells (p < 0.05). The gene product with the highest Z-score (restrictive statistical technique for selection of appropriate genes to study) was ADRBK2. Significantly, most of the overexpressed genes were related to β-adrenergic receptors. Real-time PCR analysis confirmed the up regulation observed in the microarrays, which indicated overexpression in 100% of the tumors. In oral squamous cell carcinomas, malignant cells and surrounding tissue overexpress the ADRBK2 gene.

The ATP6V1C1 gene encodes the C1 subunit of the vacuolar-ATPase (V-ATPase) proton pump. This gene is over-expressed in oral squamous cell carcinoma (OSCC) as determined by real-time quantitative polymerase chain reaction. The aim of our study was to perform an immunohistochemical study of the distribution of the C1 subunit in normal epithelium of the oral cavity and in OSCC. We analyzed the expression of the C1 subunit in eight OSCC samples and two normal oral mucosa samples using polyclonal V-ATPase C1 antibody (clone H-300). In the normal oral mucosa samples, C1 subunit staining was observed in the basal and intermediate layers of the epithelium. No staining was visible in the keratinized superfi cial layers. More intense staining was observed in the OSCC samples, with the predominant expression at the periphery of tumor nests and absence of expression in dyskeratotic areas. C1 subunit expression in tumor cells was predominantly cytoplasmic, although there was perinuclear and nuclear expression in some samples. These fi ndings demonstrate that V-ATPase is necessary for proper epithelial functioning and show its importance in the development of OSCC as evidenced by the over-expression of ATP6V1C1 in OSCC.

Objective: Interest in oral exfoliative cytology has increased with the availability of molecular markers that may lead to the earlier diagnosis of oral squamous cell carcinoma. This research aims to compare the efficacy of three different instruments (Cytobrush, curette and Oral CDx brush) in providing adequate material for molecular analysis. Methods: One hundred and four cytological samples obtained from volunteer healthy subjects were analysed using all three instruments. The clinical and demographical variables under study were age, sex and smoking habits. The three instruments were compared for their ability to obtain adequate samples and for the amount of RNA obtained using quantitative real-time polymerase chain reaction (PCR-qRT) analysis of the Abelson (ABL) housekeeping gene. Results: RNA of the ABL gene has been quantified by number of copies. Adequate samples were more likely to be obtained with a curette (90.6%) or Oral CDx (80.0%) than a Cytobrush (48.6%); P

The frequency of some Cystic Fibrosis (CF) Transmembrane Conductance Regulator gene (CFTR) mutations varies between populations. Genetic testing during newborn screening (NBS) for CF can identify less common mutations with low clinical expression in childhood and previously considered mild but not fully characterized, such as the mutation p.Val232Asp (c.695T > A). The aim of this study was to describe CF patients with the V232D mutation. We identify CF children with the V232D mutation detected by NBS and compare them with CF adults with this mutation whose diagnosis was prompted by clinical symptoms in the same period. We studied clinical, biochemical, spirometric, and prognostic features in both populations. NBS program tested 276,523 children during a period of 14 years (2003-2017) and identified 54 cases of CF. Six children (11%) had the V232D mutation. Over the same period, 5 adults (age 37.6 ± 16.29 years old) with symptoms of CF and this mutation were also diagnosed. Follow-up duration was mean 10.1 years for adults and mean 6.5 years for children. In the adult group, lung function was impaired at diagnosis in all patients (Forced Expiratory Volume1-FEV1-67.12% ± 13.09) and worsened in children tested during evolution (FEV1first: 113%; FEV1last: 64%). Pancreatic insufficiency was present in adult group, with recurrent pancreatitis in 1 present. Although with less clinical expression in children, V232D is associated with pulmonary and pancreatic involvement during adulthood and CF cannot be considered mild. This mutation is present in 11% of all patients diagnosed with CF in our region. Its inclusion in some NBS programs should be taken into account in order to improve the prognosis of affected children. SI

Distraction osteogenesis is a fundamental pillar for craniomaxillofacial reconstruction processes. Nonetheless, although the clinical, biomechanical, and histologic changes associated with distraction osteogenesis have been widely described, this is not the case with the molecular mechanisms that regulate bone synthesis in the interfragmentary gap resulting from the gradual separation of bone segments. Recent studies have attributed a decisive role to the RANK/RANKL/OPG system in regulating bone metabolism and osteoclastogenesis. Receptor activator of nuclear factor kappa beta (RANK), belonging to the tumor necrosis factor superfamily, is present in the osteoclasts. It promotes osteoclastogenesis when it binds to RANK ligand (RANKL), which is produced by the osteoblasts and other stromal cells. Osteoprotegerin (OPG) acts as a decoy receptor by binding to RANKL and preventing RANK signaling. Osteoclast activation is thus blocked and apoptosis induced. The aim of this review is to analyze the influence of the RANK/RANKL/OPG system on the bone healing and remodeling processes that occur in distraction osteogenesis, with a view to possibly developing molecular mechanisms that stimulate bone regeneration and inhibit resorption, thereby improving the clinical outcome for distraction osteogenesis.

Introduction. Hypomyelinating leukodystrophy-6 is a rare and early onset neurodegenerative disease which entails a clinical pattern of pyramidal-extrapyramidal and cerebellar involvement and it comes with a neuroimaging consisting of hypomielination, cerebellar hypoplasia and specific abnormalities in basal ganglia, particularly the absence or nearly absence of putamen and the possible loss of caudate’s volume. It is due to an alteration in tubulin and it is determined by mutations in heterocygosis in TUBB4A gene, showing complete penetrance. Case report. An 8-year-old child with history of delayed motor development, tremor, dysathria, ataxia, nystagmus, cognitive deficit and dystonia with pattern of hypomielination, vermis hypoplasia and absence of putamen. These findings, although distinctive, had been underestimated in previous evaluations and their detection determined the analyse and identification of a pathogenic variant in TUBB4A gene. Conclusions. Progressive deterioration leads the patient to total dependence or death in infancy or youth and there is no specific treatment capable of modifying its natural course.

Acidity is one of the main features of the tumors. The V-ATPase is the primary responsible for the control of tumor microenvironment by proton extrusion to the extracellular medium. The acid environment favors tissue damage, activation of destructive enzymes in the extracellular matrix, the acquisition of metastatic cell phenotypes as well as increasing the destructive capacity. The application of specific inhibitors of V-ATPases, can decrease the acidity of tumor and may allow the reduction of tumor metastasis, acting on the survival of tumor cells and prevent the phenomena of chemoresistance. Among the most important inhibitors can be distinguished benzolactone enamides (salicylihalamide), lobatamide A and B, apicularen, indolyls, oximidine, macrolactone archazolid, lobatamide C, and cruentaren. The latest generation of inhibitors includes NiK12192, FR202126, and PPI SB 242784. The purpose of this paper is to describe the latest advances in the field of V-ATPase inhibitors, describe further developments related to the classic inhibitors, and discuss new potential applications of these drugs in cancer treatment.

Oral squamous cell carcinoma is the most common neoplasia of the mouth. Downregulation of p16(INK4a) (a cyclin-dependent kinase inhibitor) has been reported for mouth cancer and it is believed that its inactivation is an early event in oral carcinogenesis. The goal of this article is to quantitatively report expression of p16(INK4a) and the state of methylation in oral squamous cell carcinoma, and evaluate its relationship with the clinical and prognostic factors, in addition to setting out a multivariate model that predicts survival. The mean expression of p16(INK4a) was 7.70 (SD=14.07) (F=0.894; P=0.449). According to the semiquantitative analysis, there were statistically significant differences, where 19 cases were negative (

OBJECTIVES Downregulation of p21{Waf1/CIP1} (a cyclin-dependent kinase inhibitor) has been reported for mouth cancer. The goal of this article is to quantitatively report expression of p21{Waf1/CIP1} and evaluate its relationship with the clinical and prognostic factors. MATERIALS AND METHODS this is a retrospective study of 68 patients diagnosed with OSCC. We constructed a tissue microarray to develop an immunohistochemical assessment of p21{Waf1/CIP1} expression. A multivariate analysis using a forward-selection stepwise regression model (Cox, 1972) for predicting survival was performed. RESULTS The quantitative expression of p21{Waf1/CIP1} showed a statistically significant relationship with the risk of lymph node metastasis, showing a higher expression in patients with homolateral single nodes of less than 3 cm (N1) (X{2}=6.58; p< 0.05). We found no statistically significant relationship with any other clinical or pathological parameters. The Cox univariate regression analysis verifies that the effect of the value of p21{Waf1/CIP1} on survival was not statistically significant (p=0.6). The best predictive multivariate Cox analysis included the covariates: recurrence, p21{Waf1/CIP1}, gender, stage, and dysplasia in the adjacent margin. All these variables showed a statistically significant relationship with survival, except p21{Waf1/CIP1}. CONCLUSION quantitative determination of p21{Waf1/CIP1} standardizes and facilitates its analysis. Although its expression increases in patients with N1 regional metastasis, the loss of p21{WAF1/CIP1} does not seem to have any relationship with the clinical and pathological variables of the tumors.

Purpose To study the gene expression profile of oral squamous cell carcinomas. Materials and Methods Gene expression profile was investigated in oral squamous cell carcinomas in 5 patients using the Atlas Glass Human 3.8 I Microarray (which detects cDNA obtained from cellular total RNA) (Clontech Laboratories, Palo Alto, CA). Data were normalized by the LOWESS method. Statistical significances of deviations from a 1:1 ratio were evaluated by t tests, with P Results Of the 3,757 genes analyzed, 322 (8.6%) were significantly overexpressed in tumoral tissue with respect to normal tissue, while 104 (2.8%) were significantly underexpressed. The affected genes fell into a wide range of functional categories. Conclusion We consider that cDNA microarrays are of clear value for investigating the biology of these tumors, and that this technology may help in the molecular classification of oral squamous cell carcinomas and in the identification of targets for gene therapy.

Myc genes are a family of proto-oncogenes whose proteins are implicated in the regulation of cell proliferation, differentiation and apoptosis, and in regulating the activity of genes involved in cell division. The aim of the present study was to establish a quantitative description of the expression of c-myc and evaluate its relationship with other clinical and prognostic factors, as well as to establish a multivariate survival prediction model. This is a retrospective study of 68 patients diagnosed with oral squamous cell carcinoma (OSCC). We constructed a tissue microarray for investigating the expression of c-myc by immunohistochemistry. Statistical analyses were carried out, and a multivariate model that predicts survival was established. The average expression of c-myc was 50.32 (SD, 26.05) with a range from 6.60 to 99.48; similar for initial and advanced tumor stages. Non-smoking patients had higher levels of c-myc, showing statistically significant differences (Kruskal-Wallis chi2=5.975; p=0.05). We found no statistically significant relationship between the quantitative expression of c-myc and any other clinical or pathological parameters. For each unit of increase of c-myc, the risk increased by 1.15 (p

Cherubism is classified within the group of benign osteo-fibrous lesions. Aside from facial deformities, it may account for major complications. It has been observed that the disease is caused by a mutation in the gene SH3BP2 (SH3-domain binding protein 2), which is located at chromosome 4pl6.3. Here we present two cases of familial cherubism, uncle and nephew, with variable clinical involvement ("Expressivity"), and one case of a woman (sister and mother, respectively), who transmitted cherubism without suffering the disease. In this article we have shown that, in familial cherubism cases, the mutation is inherited through an autosomal dominant transmission. Mutations affecting gene SH3BP2 cause variable clinical involvement (variable expressivity), involvement can be moderate, severe or may result merely in asymptomatic carriers. Since the possibility of transmission reaches 50% of chances, we believe that it is important to develop genetic counseling for both patients and carriers, in order to prevent or minimize new affected offspring.Cherubism; SH3BP2; Expressivity.

Oral Squamous Cell Carcinoma (OSCC) is biologically characterized by the accumulation of multiple genetic and molecular alterations that end up clinically characterized as a malignant neoplasm through a phenomenon known as multistep. The members of the Cip/Kip family, specifically p21 Waf 1/CIP1 , are responsible for cell cycle control, blocking the transition from phase G1 to phase S. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the keywords. The goal of this paper is to determine the relationship between p21 Waf 1/ CIP1 expression and several clinical and pathological aspects of OSCC, their relationship with p53 and HPV, as well as genetic alterations in their expression pattern, their use as a prognosis market in the evolution of precancer - ous lesions and their roles in anticancer treatments. The results of p21 WA F1/C I P1 expression in OSCC showed mixed results in terms of positivity/negativity throughout different studies. It seems that, although p21 Waf 1/CIP1 expression is controlled in a p53-dependent manner, coexpression of both in OSCC is not intrinsically related. Although the presence of HPV viral oncoproteins increases p21 Waf 1/CIP1 levels, the small number of studies, have forced us to disregard the hypothesis that HPV infected lesions that present better prognosis are due to a p21 Waf 1/CIP1 -dependent control. The role of p21 WA F1/C I P1 as cell-cycle regulator has been well described; however, its relationship to OSCC, the clinical and pathological variables of tumors, HPV and different treatments are not entirely clear. Thus, it would be very interesting to pursue further study of this protein, which may have a significant value for the diagnosis, prog nosis and therapy of this type of tumors.

Introduction. Aicardi-Goutieres syndrome is a rare progressive subacute encephalopathy of early onset - generally in the first year of life - characterised by psychomotor retardation, microcephaly, alterations in the white matter of the brain, intracranial calcifications, pleocytosis and elevated levels of interferon alpha in the cerebrospinal fluid. It is associated to an increase in the expression of genes stimulated by interferon in peripheral blood, a fact known as the interferon signature. The levels of genes stimulated by interferon has been postulated as a good biomarker, as they remain high in peripheral blood over time and are more sensitive, in comparison to determinations of interferon alpha and neopterins in cerebrospinal fluid, which descend as of one year of life. To date, mutations have been reported in seven genes that overstimulate the interferon alpha pathway, and the last to be discovered is IFIH1 (interferon induced with helicase C domain 1), with a pattern of dominant autosomal inheritance. Case report. We present the first case reported in the Hispanic literature caused by a de novo mutation in the IFIH1 gene. The clinical features, studies conducted and review of the clinical, neuroradiological and genetic aspects are described. Conclusions. The inheritance of the mutations reported for Aicardi-Goutieres syndrome was classically considered as being recessive autosomal, but these findings show that dominant autosomal mutations in the IFIH1 gene can cause the disease. As a previously unreported neuroimaging finding, it presents a lesion consisting in cystic encephalomalacia in the pons.

BCL-10 (B-cell lymphoma 10) has been linked to a pro-apoptotic gene in mucosa-associated lymphoid tissue (MALT) lymphomas. We describe the expression of BCL10 in oral squamous cell carcinoma (OSCC) and its relation to clinical, pathological and prognostic parameters. We carried out a retrospective study of 50 patients in Spain who were diagnosed with OSCC. We constructed a tissue microarray of the samples to study the expression of BCL10 using immunohistochemistry. Diffuse and homogeneous staining was observed in the nuclei and cytoplasms of most neoplastic cells of the vast majority of tumors and no significant differences were seen in different areas of the tumors. The expression was unrelated to any clinical or pathological parameters including tumor stage. The intra-class coefficient was 0.97, which indicates the minimal variability among the determinations. © 2012 The Biological Stain Commission.

Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues.This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves.Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III-IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I-II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank=6.1, P value=0.0484.Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor.

Tumoral microenvironments play a key role in the evolution of solid tumors. Tumor hypoxia is actively involved in the promotion of genetic instability, the invasive capacity of tumor cells, metastasis, and a worsening of the clinical evolution. Endogenous hypoxia markers are controlled by hypoxia-related genes, formed by HIF-1, which is related to several target genes that involve the energy metabolism, angiogenesis, and transmembrane carbonic anhydrases (CAs), mainly CA-IX that is one of the tumor-related carbonic anhydrases. The goal of this paper is to establish the role of CA-IX as a hypoxia marker in OSCC, while analyzing its expression in this type of tumors and its relationship with several clinical and pathological parameters and prognosis, evaluating its relationship with angiogenesis, other hypoxia markers, and clarifying its role in chemotherapy and radiotherapy resistance.

Vacuolar ATPases (V-ATPases) are present in specialized proton secretory cells in which they pump protons across the membranes of various intracellular organelles and across the plasma membrane. The proton transport mechanism is electrogenic and establishes an acidic pH and a positive transmembrane potential in these intracellular and extracellular compartments. V-ATPases have been found to be practically identical in terms of the composition of their subunits in all eukaryotic cells. They have two distinct structures: a peripheral catalytic sector (V1) and a hydrophobic membrane sector (V0) responsible for driving protons. V-ATPase activity is regulated by three different mechanisms, which control pump density, association/dissociation of the V1 and V0 domains, and secretory activity. The C subunit is a 40-kDa protein located in the V1 domain of V-ATPase. The protein is encoded by the ATP6V1C gene and is located at position 22 of the long arm of chromosome 8 (8q22.3). The C subunit has very important functions in terms of controlling the regulation of the reversible dissociation of V-ATPases. As Vacuolar ATPases (V-ATPases) estão presentes nas células especializadas em secreção de protões, nas quais eles são bombeados através das membranas de vários organelos intracelulares e da membrana plasmática. O mecanismo de transporte de protões é eletrogênico e estabelece um pH ácido e um potencial transmembrana positivo nestes compartimentos intracelulares e extracelulares. As V-ATPases foram encontradas em todas as células eucarióticas, praticamente idênticas em termos de composição das suas subunidades. Elas têm duas estruturas distintas: um setor periférico catalítico (V1) e uma membrana hidrofóbica (V0), responsável pela condução de protões. A atividade das V-ATPases é regulada por três mecanismos diferentes, os quais controlam a densidade de bomba, associação/dissociação de domínios V1 e V0, e a atividade secretora. A subunidade C é uma proteína de 40-kDa, localizada no domínio V1 da V-ATPase. Essa proteína é codificada pelo gene ATP6V1C e está localizada na posição 22 do braço longo do cromossomo 8 (8q22.3). A subunidade C tem funções muito importantes em termos de controle do regulamento da dissociação reversível da V-ATPase.

Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet.

A micro RNA (miRNA) is a single-stranded endogenous, non-coding RNA, with length ranging between 18 and 24 nucleotides and the ability of regulating the expression of other genes on a post-transcriptional level by means of various processes, degradation or repression of target mRNA. miRNAs play a crucial role in regulating fundamental processes such as cell cycle, differentiation and apoptosis; thus, their deregulation can affect normal cell growth and development, and even participate in carcinogenesis. The goals of this paper are: to outline the formation and functions of miRNAs; to determine their role in oral squamous cell carcinoma; to analyze the different miRNAs described and their roles as oncogenes or tumor suppressor genes, depending on their overexpression or subexpression; to describe the different polymorphisms and epigenetic alterations identified; and to determine their role in multidrug resistance.

The main cause of death in oral squamous cell carcinomas (OSCC) is metastasis. Intercellular adhesion is mediated by a family of glycoproteins called cadherins and other molecules like catenins and APC (adenomatous polyposis coli) among other. The WNT (wingless-type) gene family is a group of genes, key signaling pathway for embryonic development and oncogenesis. The goal of this paper is to describe the role of the APC gene, and its derivatives, in the carcinogenicity pathway of WNT-1, identifying its role as a tumor suppressor gene in OSCC, while describing the genetic (loss of heterozygosity and mutations) and epigenetic alterations that modulate its expression and evaluate its relationship with the clinicopathological parameters of this type of tumors. As for APC, its activity as a tumor suppressor gene appears muted on a relatively frequent basis in these tumors, either by LOH, mutations or epigenetic control mechanisms, thus resulting in a low degree of agreement between the results of different studies.

The influence of c-myc in the carcinogenic process has been previously described although in the specific case of oral tumors it has been poorly tested. Myc proteins are a family of proto-oncogenes involved in the cell proliferation regulation, differentiation and apoptosis. The goal of this paper is to describe the functions of c-myc and its role as oncogene, assessing its expression by immunohistochemistry and genetic amplification studies, and studying its relationship with tumoral clinical and pathological variables, and describing genetic and molecular interactions in OSCC.

We report three unrelated patients with congenital facial nerve palsy and chromosome 22q11 deletion, a condition hitherto poorly recognized. In the first case, facial palsy was associated with aortic coarctation, ductus arteriosus, and ostium secundum atrial septal defect. In the second case, facial palsy was associated with ostium secundum atrial septal defect, obstruction of the ureteropelvic junction, double ureteropelvic-calicial system, and distal metaphyseal widening of the forearm and leg bones. In both cases, facial palsy was the presenting feature. In the third case, an ostium secundum atrial septal defect was also present, but involvement of cranial nerves III, VI, and VIII, in addition to hypoplastic structures of cerebellar and cerebral peduncles, were the predominant features. There were no inherited deletions within chromosome band 22q11 and the de novo deletions detected in each case belonged to the paternally derived chromosome 22. Association of facial nerve palsy and congenital heart disease versus cardiofacial syndrome are different only on clinical grounds, so both conditions can be genetically identical and form part of the spectrum of defects associated with chromosome 22q11 1 deletions. We recommend investigation for chromosome 22q11 deletions in patients with complete nerve facial palsy. (J Child Neurol 2001;16:450-452).

CADASIL is a dominant autosomal inborn systemic arteriopathy, whose genetic anomaly is located in the Notch-3 gene of chromosome 19. It is clinically characterised by migraine with aura, recurrent stroke and cognitive deterioration, and is one of the causes of strokes among the young.The propositus was a 57-year-old male who presented a clinical picture of dysarthria, loss of strength in the left extremities and alterations affecting balance with dysmetry in the left extremities, related with an acute ischaemic stroke in the cerebellar peduncle. An ultrastructural study of a biopsy specimen of the skin revealed the electron-dense deposits that characterise CADASIL. The genetic analysis identified a new mutation for this disease in codon 296 of exon 6 in the Notch-3 gene that produces a change of amino acid, from glycine to cysteine in protein (p.G296C).This communication reports the case of a family with CADASIL that was a carrier of a new p.G296C mutation located in exon 6 of the Notch-3 gene.

The beta-adrenergic receptors transduce catecholamine signals to the G protein, which through a cascade of chemical reactions in cells generates highly specific parallel signals. The beta2-adrenergic receptor (ADRB2) is the most involved in the carcinogenic processes. Previous studies have determined the relationship of ADRB2 with various aspects related to cancer. Basically, it seems to be related with cell proliferation and apoptosis, chemotaxis, development of metastasis and tumor growth, and angiogenesis. The purpose of this review is to update the implications of these receptors in the pathogenesis of cancer and study the possible application of agonist drugs and/or antagonists in antitumor therapy.

Exfoliative cytology is a minimally invasive technique for obtaining oral cell specimens from patients for diagnostic purposes. Classical applications of oral cytology studies, such as oral candidiasis, have been extended to include oral precancerous and cancerous lesions. A number of analytical methods are available for studying cytology specimens. The development of molecular analysis techniques, the oral cancer etiopathogenic process, and improvements in liquid-based exfoliative cytology are leading to renewed interest in exfoliative cytology. Results sometimes are disputed, so the aim of our review was to clarify the applicability of exfoliative cytology to the diagnosis of oral precancerous and cancerous lesions.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Brush cytology has reemerged as a molecular tool for diagnosing this cancer. ATP6V1C1, one of the main genes regulating V-ATPase activity, has been implicated in metastasis and multiple drug resistance. The aim of this study was to measure ATP6V1C1 expression levels in OSCC and to evaluate the value of this test in the diagnosis and prognosis of OSCC.The differences in ATP6V1C1 expression between patients and controls were statistically significant (Mann-Whitney U test = 26, p0.001). Receiver operating characteristic (ROC) curve analysis showed an area under the curve of 0.9476, with the following diagnostic indices: sensitivity, 81.25%, specificity, 93.75%; accuracy, 87.50%; positive predictive value, 92.86%; negative predictive value, 83.33%; positive likelihood ratio, 30; and negative likelihood ratio, 0.06.Patients with OSCC and a control group of healthy individuals were studied. The clinical and demographic variables analyzed included age, sex, smoking, tumor location and tumor stage. Brush cytology samples were obtained using a cytology brush and analyzed by real-time quantitative polymerase chain reaction for ATP6V1C1 expression.It was confirmed that ATP6V1C1 levels were significantly higher in patients with OSCC than in healthy controls, with expression increasing with higher tumor stage. ROC analysis showed that the measurement of ATP6V1C1 expression levels is a highly sensitive and specific diagnostic method.

Resistance to chemotherapy agents is the main reason for treatment failure in patients with cancer. Multidrug resistance (MDR) is the primary mechanism that leads to the acquisition of the multiresistant phenotype through the overexpression of drug efflux transporters such as the P-glycoprotein (Pgp), encoded by the MDR1 gene, at the plasma membrane. Other molecules that have been implicated in drug resistance include multidrug resistance-associated proteins, glutathione S-transferase-pi, and DNA topoisomerase II. These molecules, however, cannot fully explain MDR in oral squamous cell carcinoma. Vacuolar ATPase (V-ATPase), which is largely responsible for regulating acidity in the microenvironment of solid tumors (and hence interfering with the absorption of chemotherapy drugs), seems to be the most important molecule involved in MDR in such tumors. Specific V-ATPase inhibitors, thus, may be useful, not only as coadjuvants in antitumor treatments but also as a mechanism for controlling resistance to antitumor drugs.

The development of oral squamous cell cancer (OSCC) is a multistep process involving the accumulation of multiple genetic alterations modulated by genetic pre-disposition and environmental influences such as tobacco and alcohol use, chronic inflammation, and viral infections. All of these factors can lead to a wide range of genetic and molecular alterations that can be detected using a range of molecular studies. The alterations mostly affect two large groups of genes: oncogenes and tumor suppressor genes, which can be either inactivated or overexpressed through mutations, loss of heterozygosity, deletions, or epigenetic modifications such as methylation. Other molecules that are closely associated with tumor pathogenesis and prognosis also exist and warrant further study. Important advances in molecular biology are helping to shed light on oral cancer and thus aiding in the early diagnosis and development of new personalized treatment approaches. The purpose of the review is to explore the genetic and molecular alterations associated with OSCC.

Introduccion. Los sindromes de microdelecion y microduplicacion 3q29 se caracterizan por una marcada heterogeneidad fenotipica, y el retraso del desarrollo y la discapacidad intelectual de grado leve-moderado son las manifestaciones clinicas mas frecuentes. Casos clinicos. Dos pacientes con aberraciones cromosomicas reciprocas en la region 3q29. La paciente con la microdelecion 3q29 presenta dificultades de aprendizaje, microcefalia limite, dismorfismo facial leve, deficit atencional e impulsividad, y rasgos ansiosos y obsesivos. El paciente con la microduplicacion 3q29 reciproca presenta dificultades de aprendizaje, dismorfismo facial leve y un perfil conductual disruptivo no asociado previamente con esta duplicacion. Conclusion. Se comparan los fenotipos de estos pacientes y se revisa la bibliografia de pacientes pediatricos con microdeleciones y microduplicaciones 3q29.