NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva.

Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance, we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and quantitative methylation specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage design consisting of discovery and prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. Promoter methylation of KIF1A (κ = 0.64), HOXA9 (κ = 0.60), NID2 (κ = 0.60), and EDNRB (κ = 0.60) had a moderate to substantial agreement with clinical diagnosis in the discovery screen. HOXA9 had 68% sensitivity, 100% specificity, and a 0.81 Area Under the Curve (AUC). NID2 had 71% sensitivity, 100% specificity, and a 0.79 AUC. In the prevalence screen, HOXA9 (κ = 0.82) and NID2 (κ = 0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity, and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity, and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity, and a 0.97 AUC. In saliva, from OSCC cases and controls, HOXA9 had 75% sensitivity, 53% specificity, and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity, and a 0.73 AUC. This phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies.

Monitorización inmunológica en mujeres con aborto recurrente / Immunological monitoring in women with recurrent spontaneous abortions

Para evaluar la prevalencia de alteraciones inmunológicas en pacientes con aborto espontáneo recurrente realizamos un estudio retrospectivo transversal. Las mujeres estudiadas habían sido evaluadas previamente mediante cariotipo de pareja y ecografía para investigar alteración anatómica. La monitorización inmunológica de rutina incluyó anticuerpos antifosfolípidos (in = 333), anticuerpos anticardiolipina (ACA), anticoagulante lúpico], anticuerpos anti-beta-2 glucoproteína-I (n = 139) [anticuerpos antinucleares (n = 333), anticuerpos antitiroideos (n = 180) y evaluación del porcentaje de células natural killer (NK) en sangre periférica (n = 189) en 333 pacientes consecutivas con 2 o más (intervalo 2-12) abortos espontáneos recurrentes. Se detectaron anticuerpos antifosfolípidos (ACA a valor moderado-alto o anticoagulante lúpico) en un 15,9% de pacientes. Un 6% de las pacientes tuvo anticuerpos antinucleares a título 1:160 o mayor. Se observó un porcentaje elevado de linfocitos CD56+/CD16+CD3­ (> 18%) en el 11,1% de las pacientes. Se documentó positividad de anticuerpos antitiroideos en el 4% de las mujeres. Globalmente, un 28,5% de las mujeres tuvo al menos una alteración inmunológica de las estudiadas. En un estudio realizado en mujeres con aborto espontáneo recurrente se observaron alteraciones autoinmunitarias y aloinmunitarias que involucran distintos autoanticuerpos y células NK de sangre periférica (AU)

We performed a retrospective cross-sectional study to ascertain the prevalence of immunological abnormalities in women with recurrent spontaneous abortions (RSA). The women had previously undergone karyotyping of the couple and ultrasonography to investigate anatomic uterine anomalies before immunological study. Routine immunologic monitoring for circulating antiphospholipid antibodies (aPL, n=333) [anticardiolipin antibodies (aCL), lupus anticoagulant (LA)], anti-beta-2 glycoprotein-I antibodies (n=139), antinuclear antibodies (n=333), antithyroid antibodies (n=180) and percentages of natural killer (NK) cells in peripheral blood (n=189) was carried out in 333 consecutive patients with two or more (range 2-12) RSA. aPL positivity (mean-high value aCL or LA) was 15.9%. The frequency of positive antinuclear antibody tests at a titer of 1:160 or higher was 6%. Elevated levels of CD56+/CD16+CD32 lymphocytes (>18%) were observed in 11.1% of the patients studied. Anti-thyroid antibody positivity was found in 4% of women. Overall, 28.5% of women had at least one immunological abnormality. Women with RSA had significant autoimmune and alloimmune alterations involving functionally distinct autoantibodies and peripheral blood NK cells (AU)

Síndrome de anticuerpos antifosfolípidos: asociación con abortos de repetición e infertilidad / Antiphospholipid syndrome: Association with abortions and infertility

El síndrome de anticuerpos antifosfolípidos se caracteriza por la presencia de eventos trombóticos y abortos recurrentes en asociación con anticuerpos anticardiolipina y/o anticoagulante lúpico. Los anticuerpos anticardiolipina se detectan por técnica de ELISA, mientras que el anticoagulantelúpico mediante técnicas coagulimétricas. El aborto recurrente asociado a anticuerpos antifosfolípidos es una entidad tratable. Se piensa que, además de herramientas diagnósticas, los anticuerpos antifosfolípidos son elementos patogénicos. La demostración más fuerte de su papel patogénico radica en su habilidad para inducir reabsorción fetal cuando son infundidos pasivamente a animales durante la gestación. El tratamiento de las mujeres embarazadas con síndrome de anticuerpos antifosfolípidos sebasa en el uso de antiagregantes y anticoagulantes (ácido acetilsalicílico y heparina) para prevenir la trombosis en la circulación uteroplacentaria. El tratamiento con estos medicamentos y la monitorización cuidadosa del embarazo han aumentado la supervivencia fetal. Incluso así, aún no hay un consenso general con respecto al significado patogénico de estos anticuerpos y el tratamiento de las pacientes.La deficiencia de la implantación embrionaria es un vínculo común entre la infertilidad y los abortos recurrentes. Por ello se ha tratado de vincular también la presencia de anticuerpos antifosfolípidos con el desarrollo de fallos en la implantación que se observan tras la fecundación in vitro ytransferencia de embriones. En este trabajo hacemos una extensa revisión de los datos publicados sobre el tratamiento del fallo reproductivo asociado a la presencia de anticuerpos antifosfolípidos con la finalidad de dotar a los clínicos que tratan a estas pacientes con información actualizada para su utilización en la práctica clínica

The antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent pregnancy loss in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. Recurrent pregnancy loss associated with antiphospholipid antibodies is now considered a treatable clinical condition. Rather than being diagnostic tools only, antiphospholipid antibodies are thought to be pathogenic. The strongest demonstration of their pathogenic role lies in the ability to induce fetal resorptions when passively infused in pregnant naive animals. The management of pregnant patients with antiphospholipid syndrome is mainly based on the use of antiaggregant/anticoagulant agents (with acetylsalicylic acid and heparin) to prevent thrombosis in the uteroplacental circulation. Interventionswith these drug therapies and monitored pregnancy have increased fetal survival. However, this is still a matter of debate with no general agreement with respect to both pathophysiological significance of the presence of antiphospholipid antibodies and patient management (AU)

[Familial Pitt-Rogers-Danks: two new cases]. / Síndrome de Pitt-Rogers-Danks familiar: dos nuevos casos.

INTRODUCTION AND CLINICAL CASES: The Pitt Rogers Danks syndrome is characterized by prenatal and postnatal retardation of growth, mental retardation, microcephaly, convulsions and a peculiar facies. It is believed to represent a clinical variant of the Wolf Hirschhorn syndrome, since there is a deletion in the 4p16.3 region in both syndromes. We report two cases in the same family caused by maternal mal segregation of a 4:8 balanced translocation. We describe the clinical characteristics, investigations done and a review of the literature.

Molecular analysis of a gestation consisting of a complete hydatidiform mole and normal dizygotic twin.

OBJECTIVE: To identify a twin pregnancy consisting of a complete mole and coexistent fetus by means of molecular cytogenetics and DNA polymorphisms. STUDY DESIGN: Seven highly polymorphic DNA markers were used to establish the androgenetic origin of a complete hydatidiform mole that coexisted with a normal 46,XY fetus. Cytogenetic analysis of mole nuclei was performed with centromeric probes, demonstrating a 46,XX constitution. RESULTS: Molar tissue was diploid with two X chromosomes, possibly due to chromosome doubling after monospermic fertilization of an ovum with inactivated or absent nucleus. CONCLUSION: Although contamination with maternal tissue may be difficult to avoid, molecular markers provide the possibility of distinguishing between a complete hydatidiform mole and coexisting normal fetus versus a partial mole, with methods that can be performed antenatally. This distinction is important since in the first case up to 24% of fetuses described in the literature have been viable, and the risk of subsequent development of persistent trophoblastic tumor in patients with a complete mole and a coexisting fetus is considerably higher than in patients with a single, complete hydatidiform mole.

Immunological abnormalities in primary APS evolving into SLE: 6 years follow-up in women with repeated pregnancy loss.

We have performed a prospective study to determine the prevalence of immunological abnormalities and the evolution from primary antiphospholipid syndrome (APS) into systemic lupus erythematosus (SLE) in women who had had unexplained repeated pregnancy loss (PL) and APS. Of 105 women with abortions or fetal deaths, 33(31%) fulfilled criteria for APS. Among these patients with primary APS, 24% had antinuclear antibodies (ANA), 91% had elevated circulating immune complexes (CIC), 70% had low total haemolytic complement (CH100), 52% had low levels of complement 4 (C4) and 30% had low levels of complement 3 (C3), in a significantly higher prevalence than women whose pregnancies were successful (control group). Through out a 6 y follow-up, 3 (9%) of the patients with APS who had autoimmune related abnormalities when entered into the study developed features of lupus like disease (LLD) or fullblown SLE. Our findings suggest that women with unexplained repeated PL with APS who presented with positive ANA, high levels of CIC, low levels of CH100, C3 and C4, may define a subset of patients exhibiting immunological alterations similar to those of SLE. These parameters may help in the assessment of prognosis in APS patients with PL. Those patients should be carefully surveyed with regard to the development of connective tissue diseases.