Estrogen and Progesterone Receptors Are Dysregulated at the BPH/5 Mouse Preeclamptic-Like Maternal-Fetal Interface.

The etiopathogenesis of preeclampsia, a leading hypertensive disorder of pregnancy, has been proposed to involve an abnormal circulating sex hormone profile and misexpression of placental estrogen and progesterone receptors (ER and PR, respectively). However, existing research is vastly confined to third trimester preeclamptic placentas. Consequently, the placental-uterine molecular crosstalk and the dynamic ER and PR expression pattern in the peri-conception period remain overlooked. Herein, our goal was to use the BPH/5 mouse to elucidate pre-pregnancy and early gestation Er and Pr dynamics in a preeclamptic-like uterus. BPH/5 females display low circulating estrogen concentration during proestrus, followed by early gestation hypoestrogenemia, hyperprogesteronemia, and a spontaneous preeclamptic-like phenotype. Preceding pregnancy, the gene encoding Er alpha (Erα, Esr1) is upregulated in the diestrual BPH/5 uterus. At the peak of decidualization, Esr1, Er beta (Erß, Esr2), and Pr isoform B (Pr-B) were upregulated in the BPH/5 maternal-fetal interface. At the protein level, BPH/5 females display higher percentage of decidual cells with nuclear Erα expression, as well as Pr downregulation in the decidua, luminal and glandular epithelium. In conclusion, we provide evidence of disrupted sex hormone signaling in the peri-conception period of preeclamptic-like pregnancies, potentially shedding some light onto the intricate role of sex hormone signaling at unexplored timepoints of human preeclampsia.

Disruption Of Non-COVID-19 Health Care In Latin America During The Pandemic: Effects On Health, Lessons For Policy.

COVID-19 had severe direct and indirect effects on health and well-being in Latin America. To understand the extent to which disruptions among non-COVID-19-related health services affected population health, we used administrative data from the period 2015-21 to examine public hospital discharges and mortality for conditions amenable to health care in four Latin American countries: Brazil, Ecuador, Mexico, and Peru. Between March 2020 and December 2021, hospitalization rates for these conditions declined by 28 percent and mortality rates increased by 15 percent relative to prepandemic years. Noncommunicable diseases accounted for 89 percent of this rise in mortality. The poorest states in each country experienced relatively larger increases in mortality. Our results, which focus on the health effects of service disruption, suggest that maintaining health care services in this region during the pandemic could have avoided at least 96,000 deaths. Policies should focus on maintaining essential health care services during emergencies, particularly for patients with noncommunicable diseases, and on minimizing negative consequences by ensuring coordinated and continuous care; leveraging alternative modalities of care, such as telemedicine; broadening the role of nonphysician health care workers; and expanding options for medication delivery.

Functional Pro-metastatic Heterogeneity Revealed by Spiked-scRNAseq Is Shaped by Cancer Cell Interactions and Restricted by VSIG1.

How cells with metastatic potential, or pro-metastatic states, arise within heterogeneous primary tumors remains unclear. Here, we have used one index primary colon cancer to develop spiked-scRNAseq to link omics-defined single-cell clusters with cell behavior. Using spiked-scRNAseq we uncover cell populations with differential metastatic potential in which pro-metastatic states are correlated with the expression of signaling and vesicle-trafficking genes. Analyzing such heterogeneity, we define an anti-metastatic, non-cell-autonomous interaction originating from non-/low-metastatic cells, and identify membrane VSIG1 as a critical mediator of this interaction. VSIG1 acts to restrict the development of pro-metastatic states autonomously and non-cell autonomously, in part by inhibiting YAP/TAZ-TEAD signaling. As VSIG1 re-expression is able to reduce metastatic behavior from multiple colon cancer cell types, the regulation of VSIG1 or its effectors opens new interventional opportunities. In general, we propose that crosstalk between cancer cells, including the action of VSIG1, dynamically defines the degree of pro-metastatic intra-tumoral heterogeneity.

Seroprevalencia de enfermedad de Lyme en el suroccidente de Asturias / Seroprevalence of Lyme disease in southwest Asturias

INTRODUCCIÓN: Para la correcta interpretación de los marcadores serológicos de la enfermedad de Lyme es muy importante conocer la tasa de infección en el entorno. El objetivo de este estudio fue conocer la prevalencia de anticuerpos específicos frente a Borrelia burgdorferi en una comarca rural del norte de España. MÉTODOS: Se investigó la presencia de anticuerpos IgG frente a B. burgdorferi mediante un método inmunoenzimático cualitativo en el suero de 1.432 personas divididas en 3 grupos: 316 donantes de sangre, 432 individuos que acudieron al hospital sin causa infecciosa y 684 a los que se solicitó una serología de Lyme como parte del diagnóstico diferencial. En estos últimos se registró la presencia o ausencia de factor de riesgo ocupacional. RESULTADOS: Se detectaron anticuerpos frente a B. burgdorferi en 189 (13,2%) individuos: 16 (5,1%) donantes de sangre, 62 (14,4%) personas que acudían al hospital sin causa infecciosa y 111 (16,2%) personas con diagnóstico diferencial de enfermedad de Lyme (p < 0,0001). En las personas con factor de riesgo ocupacional, la prevalencia fue del 23,5%, cifra que llegó al 45,8% en hombres mayores de 65 años. CONCLUSIONES: La prevalencia en este estudio es alta y superior a zonas con características similares de nuestro país, pero está en la media de lo publicado en otras regiones europeas. La prevalencia en donantes de sangre es menor que en los otros grupos estudiados. La edad avanzada, el sexo masculino y las prácticas de riesgo ocupacional se relacionan con una mayor prevalencia de enfermedad de Lyme

INTRODUCTION: To correctly interpret the serological markers of Lyme disease, it is very important to determine the region's infection rate. The aim of this study was to ascertain the prevalence of specific antibodies against Borrelia burgdorferi in a rural district in northern Spain. METHODS: The presence of IgG antibodies against B. burgdorferi was determined by qualitative enzyme immunoassay in the serum of 1,432 people divided into 3 groups: 316 blood donors, 432 individuals who attended the hospital without infection and 684 for whom Lyme serology testing was specifically requested as part of a differential diagnosis. In the latter group, the presence or absence of an occupational risk factor was recorded. RESULTS: Antibodies against B. burgdorferi were detected in 189 individuals (13.2%): 16 (5.1%) in the blood donors group, 62 (14.4%) in subjects who attended hospital without infection and 111 (16.2%) in subjects in whom a differential diagnosis of Lyme disease was requested (p < 0.0001). In subjects with an occupational risk factor, the prevalence was 23.5%, peaking at 45.8% in men over 65 years. CONCLUSIÓN: Our study showed a high prevalence of antibodies against B. burgdorferi and higher than that seen in other areas with similar characteristics in Spain. However, our results are similar to those published from other European regions. The prevalence in the blood donors group was lower than that observed in the other groups. Older age, the male gender and occupational risks were associated with a higher prevalence of Lyme disease

Seroprevalence of Lyme disease in southwest Asturias. / Seroprevalencia de enfermedad de Lyme en el suroccidente de Asturias.

INTRODUCTION: To correctly interpret the serological markers of Lyme disease, it is very important to determine the region's infection rate. The aim of this study was to ascertain the prevalence of specific antibodies against Borrelia burgdorferi in a rural district in northern Spain. METHODS: The presence of IgG antibodies against B. burgdorferi was determined by qualitative enzyme immunoassay in the serum of 1,432 people divided into 3groups: 316 blood donors, 432 individuals who attended the hospital without infection and 684 for whom Lyme serology testing was specifically requested as part of a differential diagnosis. In the latter group, the presence or absence of an occupational risk factor was recorded. RESULTS: Antibodies against B. burgdorferi were detected in 189 individuals (13.2%): 16 (5.1%) in the blood donors group, 62 (14.4%) in subjects who attended hospital without infection and 111 (16.2%) in subjects in whom a differential diagnosis of Lyme disease was requested (p < 0.0001). In subjects with an occupational risk factor, the prevalence was 23.5%, peaking at 45.8% in men over 65 years. CONCLUSION: Our study showed a high prevalence of antibodies against B. burgdorferi and higher than that seen in other areas with similar characteristics in Spain. However, our results are similar to those published from other European regions. The prevalence in the blood donors group was lower than that observed in the other groups. Older age, the male gender and occupational risks were associated with a higher prevalence of Lyme disease.

The protein secretion modulator TMED9 drives CNIH4/TGFα/GLI signaling opposing TMED3-WNT-TCF to promote colon cancer metastases.

How cells in primary tumors initially become pro-metastatic is not understood. A previous genome-wide RNAi screen uncovered colon cancer metastatic suppressor and WNT promoting functions of TMED3, a member of the p24 ER-to-Golgi protein secretion family. Repression of canonical WNT signaling upon knockdown (kd) of TMED3 might thus be sufficient to drive metastases. However, searching for transcriptional influences on other family members here we find that TMED3 kd leads to enhanced TMED9, that TMED9 acts downstream of TMED3 and that TMED9 kd compromises metastasis. Importantly, TMED9 pro-metastatic function is linked to but distinct from the repression of TMED3-WNT-TCF signaling. Functional rescue of the migratory deficiency of TMED9 kd cells identifies TGFα as a mediator of TMED9 pro-metastatic activity. Moreover, TMED9 kd compromises the biogenesis, and thus function, of TGFα. Analyses in three colon cancer cell types highlight a TMED9-dependent gene set that includes CNIH4, a member of the CORNICHON family of TGFα exporters. Our data indicate that TGFA and CNIH4, which display predictive value for disease-free survival, promote colon cancer cell metastatic behavior, and suggest that TMED9 pro-metastatic function involves the modulation of the secretion of TGFα ligand. Finally, TMED9/TMED3 antagonism impacts WNT-TCF and GLI signaling, where TMED9 primacy over TMED3 leads to the establishment of a positive feedback loop together with CNIH4, TGFα, and GLI1 that enhances metastases. We propose that primary colon cancer cells can transition between two states characterized by secretion-transcription regulatory loops gated by TMED3 and TMED9 that modulate their metastatic proclivities.

In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases.

How metastases develop is not well understood and no genetic mutations have been reported as specific metastatic drivers. Here we have addressed the idea that epigenetic reprogramming by GLI-regulated pluripotent stemness factors promotes metastases. Using primary human colon cancer cells engrafted in mice, we find that transient expression of OCT4, SOX2, KLF4 +/- cMYC establishes an enhanced pro-metastatic state in the primary tumor that is stable through sequential engraftments and is transmitted through clonogenic cancer stem cells. Metastatic reprogramming alters NANOG methylation and stably boosts NANOG and NANOGP8 expression. Metastases and reprogrammed EMT-like phenotypes require endogenous NANOG, but enhanced NANOG is not sufficient to induce these phenotypes. Finally, reprogrammed tumors enhance GLI2, and we show that GLI2(high) and AXIN2(low), which are markers of the metastatic transition of colon cancers, are prognostic of poor disease outcome in patients. We propose that metastases arise through epigenetic reprogramming of cancer stem cells within primary tumors.

PPARß/δ and PPARγ maintain undifferentiated phenotypes of mouse adult neural precursor cells from the subventricular zone.

The subventricular zone (SVZ) is one of the main niches of neural stem cells in the adult mammalian brain. Stem and precursor cells in this region are the source for neurogenesis and oligodendrogesis, mainly in the olfactory bulb and corpus callosum, respectively. The identification of the molecular components regulating the decision of these cells to differentiate or maintain an undifferentiated state is important in order to understand the modulation of neurogenic processes in physiological and pathological conditions. PPARs are a group of transcription factors, activated by lipid ligands, with important functions in cellular differentiation and proliferation in several tissues. In this work, we demonstrate that mouse adult neural precursor cells (NPCs), in situ and in vitro, express PPARß/δ and PPARγ. Pharmacological activation of both PPARs isoforms induces proliferation and maintenance of the undifferentiated phenotype. Congruently, inhibition of PPARß/δ and PPARγ results in a decrease of proliferation and loss of the undifferentiated phenotype. Interestingly, PPARγ regulates the level of EGFR in adult NPCs, concurrent with it is function described in embryonic NPCs. Furthermore, we describe for the first time that PPARß/δ regulates SOX2 level in adult NPCs, probably through a direct transcriptional regulation, as we identified two putative PPAR response elements in the promoter region of Sox2. EGFR and SOX2 are key players in neural stem/precursor cells self-renewal. Finally, rosiglitazone, a PPARγ ligand, increases PPARß/δ level, suggesting a possible cooperation between these two PPARs in the control of cell fate behavior. Our work contributes to the understanding of the molecular mechanisms associated to neural cell fate decision and places PPARß/δ and PPARγ as interesting new targets of modulation of mammalian brain homeostasis.

MMSE items that predict incident delirium and hypoactive subtype in older medical inpatients.

Because hypoactive delirium is especially under-recognized, we analyzed which Mini-Mental State Examination (MMSE) items predicted incident delirium and its hypoactive motor presentation. Over a 1-year period, older medical inpatients (n=291) were consecutively screened on admission with the Confusion Assessment Method-Spanish (CAM-S) to exclude prevalent delirium. Nondelirious patients were evaluated the same day with the MMSE, followed by daily ratings with the CAM-S. Those who became CAM-S positive were rated using the Delirium Rating Scale-Revised-98 to assess severity and motor subtype. Disorientation to time (OR 4.4, 95% CI 1.7-11.1) and place (OR 3.8, 95% CI 1.7-8.2) at admission were risk factors for delirium at follow-up and together correctly classified 88.3% of subjects as to delirium status. Disorientation to time and place, and visuoconstructional impairment were each associated with either hypoactive or mixed subtype (p<0.05 χ(2) test). Simple bedside evaluation of cognitive function in nondelirious patients revealed deficits that detected patients at risk for developing incident delirium at follow-up (especially hypoactive or mixed). We recommend patients with orientation deficits be monitored closely for emergence of delirium. A separate evaluation for possible dementia or other causes of cognitive impairment at admission should be considered too.

Expresión diferencial de genes asociados a carcinoma de próstata / Differential expression of genes associated with prostate carcinoma

Objetivo: La introducción del Antígeno Prostático Específico (APE) como herramienta de uso masivo en la detección precoz de cáncer prostático (CaP), parece ser al menos parcialmente responsable de la disminución en la mortalidad observada en el último tiempo. Sin embargo, el APE tiene una baja especificidad como marcador de cáncer, especialmente en el rango de 4 a 10 ng/ml donde existe una alta sobreposición con otras patologías de mayor prevalencia como por ejemplo, Hiperplasia Prostática Benigna (HPB). Es por esto, que existe una búsqueda constante de nuevos marcadores. Nuestro objetivo fue caracterizar el perfil de expresión génica del CaP utilizando microarray. Material y métodos: Doce casos de CaP con PSA <10 ng/ml y 4 casos con PSA >10 ng/ml fueron seleccionados prospectivamente para análisis de microarray para 96 genes característicos de tejido prostático. Los análisis se efectuaron por el método de Hierarchical Clustering y se realizó Transcripción Reversa y Reacción de Polimerasa en Cadena para confirmar la información obtenida mediante microarray. Además, se evaluó la presencia en sangre periférica de los genes sobre-expresados en tejido y que pudieran ser marcadores sistémicos de CaP. Resultados: Se definieron 13 genes basándose en su alta expresión, los cuales se agruparon en NCOA4/NDRG1, LDHA/LIM/GSTP1 y KLK2/KLK4 y estos con CALR y CSTB. Los genes SPARCL1, KLK3(PSA), ARSDR1 y ACPP se ordenaron en ramas independientes. El gen ACPP (fosfatasa ácida prostática) fue el más independientemente sobreexpresado. Realizamos RT-PCR para ACPP en 15 tumores primarios y sangre periférica observando señal positiva en 10 (71 por ciento) de 14 casos analizados. Conclusiones: Nuestros resultados indican que el gen ACPP se encuentra sobreexpresado a nivel molecular en tumor primario y sangre periférica, convirtiéndolo en un potencial marcador de CaP con niveles de PSA <10 ng/ml.

Objective: The introduction of prostate specific antigen (PSA) as a screening tool for early detection of prostate cancer (CaP), seems to take a role in being responsible for the decreasing of mortality observed in the last time. Nevertheless, the APE has a low specificity like cancer marker, especially in the rank from 4 to 10 ng/ml where a high superposition with other pathologies of greater prevalence like Benign Prostate Hiperplasia (HPB) exists. This is why there is a constant research for new markers. Our objective was to characterize the gene expression profile of prostate using microarray. Material and Methods: Twelve cases of CaP with PSA <10 ng/ml and 4 cases with PSA >10 ng/ml were prospectively selected for microarray analysis for 96 genes characteristic of prostate tissue. The analysis was performed by the method of Hierarchical Clustering and performed reverse transcription polymerase chain reaction to confirm the information obtained by microarray. We assessed the presence in peripheral blood of over-expressed genes in tissue that could become in systemic markers of PC. Results: We identified 13 genes based on their high expression, which were grouped into NCOA4/NDRG1, LDHA/LIM/GSTP1 and KLK2/KLK4 and those with CALR and CSTB. Genes SPARCL1, KLK3 (PSA) and ACPP ARSDR1 were ordered in separate branches. The ACPP gene (prostatic acid phosphatase) was overexpressed more independently. We RT-PCR for ACPP in 15 primary tumors and peripheral blood positive signal observed in 10 (71per cent) of 14 cases analyzed. Conclusions: Our results indicate that the ACPP gene is overexpressed in a molecular level in primary tumor and peripheral blood, making it a potential marker for prostate cancer with PSA levels <10 ng/ml.

Relationship between cognitive status at admission and incident delirium in older medical inpatients.

To evaluate the relationship between cognitive status and incident delirium, 291 geriatric patients on internal medicine wards were evaluated on admission with the Mini-Mental State Examination (MMSE) and Confusion Assessment Method-Spanish. Those with incident delirium were assessed using the Delirium Rating Scale-Revised-98 (DRS-R98). Delirium incidence was 11.7%, and 82 patients (28.2%) had cognitive deficits on MMSE. As cognitive impairment worsened, the risk for delirium increased linearly, and for each unit of MMSE worsening the DRS-R98 severity score worsened 0.4 points (F=5.39, df=1, p=0.027). Optimal MMSE cutoff score from receiver-operating characteristic curve analysis was 24.5. Even mild cognitive deficits increase delirium risk and severity.

Restauraciones cerámicas: cómo cementarlas? / Ceramic restorations: how to cement them?

En la actualidad ningún material odontológico de uso indirecto sufrió mayor evolución que las cerámicas. El aumento del contenido cristalino mejoró sus propiedades mecánicas, aumentando las opciones de sus indicaciones clínicas. Por lo tanto, esas alteraciones en la composición llevaron a una diferenciación de los procedimientos para la cementación. Anteriormente, la cementacion adhesiva era obligatoria para todas las cerámicas, lo que actualmente ya no es una verdad absoluta. De esta manera, el objetivo de este trabajo de revisión de literatura es establecer el protocolo más indicado para la cementación de las diversas categorías de sistemas cerámicos, teniendo como base las características estructurales de cada material, dando los subsídios para elegir el correcto tratamiento de superficie, agente cementante y sistema adhesivo.

At the present time no dental material for indirect restorations developed more than ceramics. The augmented crystalline content improved their mechanical properties increasing their range of clinical indications. However, these composition alterations carried to different surface treatments protocols for cementation. Previously, the adhesive luting was the standard procedure for all ceramics; nowadays these differences in composition represent a challenge for the clinician, regarding the surface treatment and luting procedures. Thus, the objective of this revision is to establish the most suitable protocol for surface treatment and cementation of several ceramic systems, based on the structural characteristics of each material, giving assistance for a correct choice of the correct surface treatment, luting agent and adhesive system.

Fractura dental con invasión del espacio biológico - una conducta multidisciplinar / Tooth fracture with biologic width violation - multidisciplinary conduct

Las fracturas coronarias constituyen problemas dentales frecuentes, especialmente en los niños y los adolescentes. Cuando ocurre, particularmente en la región anterior, el tratamiento rehabilitador tiene la función de recuperar la función y la estética de los dientes que fueron dañados por el trauma. El recubrimiento del fragmento, cuando es posible, crea una respuesta emocional positiva en el paciente y simplifica el mantenimiento de la oclusión original. En este caso, los autores exponen el tratamiento de una fractura oblicua de corona-raíz en el incisivo lateral superior con invasión del espacio biológico. Tres años después del tratamiento, el diente mostró función normal, estética favorable y una buena salud periodontal. Podemos concluir que la técnica de recubrimiento del fragmento ofrece la posibilidad de una rehabilitación estética y funcional con características más semejantes a la dentición natural, teniendo siempre que ser considerada como una de las alternativas de tratamiento para dientes fracturados, donde se tenga el fragmento dental.

Localization and developmental regulation of a dispersed gene family 1 protein in Trypanosoma cruzi.

The dispersed gene family 1 (DGF-1) is the fifth largest gene family in the Trypanosoma cruzi genome, with over 500 members (11). Many of the predicted DGF-1 protein products have several transmembrane domains and N-glycosylation and phosphorylation sites and were thought to localize in the plasma membrane. Here, we report that affinity-purified antibodies against a region of one of these proteins (DGF-1.2) localized it intracellularly in different stages of the parasite. DGF-1.2 is more abundant in the amastigote stage than in trypomastigotes and epimastigotes, as detected by immunofluorescence and Western blot analyses. The protein changed localization during intracellular or extracellular differentiation from the trypomastigote to the amastigote stage, where it finally localized to small bodies in close contact with the inner side of the amastigote plasma membrane. DGF-1.2 did not colocalize with markers of other subcellular organelles, such as acidocalcisomes, glycosomes, reservosomes, lipid droplets, or endocytic vesicles. During extracellular differentiation, the protein was detected in the culture medium from 0 to 22 h, peaking at 14 h. The presence of DGF-1.2 in the differentiation culture medium was confirmed by mass spectrometry analysis. Finally, when epimastigotes were subjected to starvation, there was a decrease in the labeling of the cells and, in Western blots, the appearance of bands of lower molecular mass, suggesting its cleavage. These results represent the first report of direct immunodetection and developmental expression and secretion of a DGF-1 protein.

Rehabilitación estética por medio de facetas directas-presentación de casos clínicos / Aesthetic rehabilitation through direct facets - report of cases

En la actualidad, la sociedad prácticamente exige una uniformidad de las características relacionadas con la apariencia física de las personas, lo que hace aumentar la búsqueda por los tratamientos que proporcionen un aspecto más agradable, vinculado a técnicas eficientes y seguras. Las alteraciones dentarias de color, de forma, textura y/o posición contribuyen de modo desfavorable, principalmente en los dientes anteriores, para una armonía facial. El uso de las facetas estéticas, directamente en la boca, es cada vez más enfatizado debido a evolución de los materiales restauradores y de la técnica adhesiva, ofreciendo una mejor relación costo/beneficio para el paciente. El objetivo del presente artículo es presentar casos clínicos en los cuales el tratamiento con facetas directas es una alternativa de tratamiento eficaz, reversible y de fácil realización.

At present, society practically demands uniformity of features in relation to physical appearance, resulting in an increasing number of persons seeking treatment that will provide them with a more pleasant visual appearance, linked to efficient and safe techniques. Alterations in tooth shade, shape, texture and/or position, particularly of anterior teeth, contribute unfavorably to facial harmony. Aesthetic facets placed directly in the mouth have been increasingly emphasized, due to the development of restorative materials and adhesive techniques, offering the patient an even better cost/benefit ratio. The aim of this article is to present clinical cases in which the direct facet was shown to be an efficient, reversible and easy to perform alternative treatment.

Reprimo as a potential biomarker for early detection in gastric cancer.

PURPOSE: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary. EXPERIMENTAL DESIGN: To search for these biomarkers, we evaluated the DNA methylation patterns of 24 genes by Methylation-specific PCR in primary tissues from 32 retrospectively collected gastric cancer cases (testing group). Correlation between methylation and gene expression was evaluated in the MKN-45 cell line after treatment with 5-aza-2'-deoxycytidine. The most frequently hypermethylated genes were next evaluated in primary tissues and plasma samples from 43 prospectively collected gastric cancer cases as well as plasma samples from 31 asymptomatic age- and gender-matched controls (validation group). RESULTS: In the testing group, 11 genes were hypermethylated in at least 50% of cases (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, 3OST2, p14, p15, DAPK, and p16). Eight genes (BRCA1, p73, RARbeta, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) were statistically associated with a particular variant of gastric cancer, the signet-ring cell type (P = 0.03). Seven genes (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, and 3OST2) were next evaluated in the validation group. We confirm the high frequency of methylation in primary tumors for all seven genes. However, only APC and Reprimo were frequently methylated in pair plasma samples. In asymptomatic controls, only Reprimo was infrequently methylated in comparison with plasma from gastric cancer cases (P < 0.001). CONCLUSION: Our results identified specific methylation profile associated to signet-ring cell-type histology and aberrant hypermethylation of Reprimo as a potential biomarker for early detection of gastric cancer.

DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis.

Diffuse type gastric carcinoma is the most aggressive type of gastric cancer. This type of tumor is not preceded by precancerous changes and is associated with early-onset and hereditary syndromes. To test the hypothesis that DNA methylation profile would be useful for molecular classification of the diffuse type gastric carcinoma, DNA methylation patterns of the CpG Island of 17 genes were studied in 104 cases and 47 normal adjacent gastric mucosa by Methylation-specific PCR, Immunohistochemistry and Hierarchical clustering analysis. The most frequent methylated genes were FHIT, E-cadherin, BRCA1 and APC (>50%), followed by p14, p16, p15, p73, MGMT and SEMA3B (20-49%). Hierarchical clustering analysis reveals four groups with different clinical features. The first was characterized by hypermethylation of BRCA1 and younger age (<45 years old), and the second by hypermethylation of p14 and p16 genes, male predominance and Epstein-Barr virus infection. The third group was characterized by hypermethylation of FHIT and antrum located tumors and the fourth was not associated with any clinical variables. In normal adjacent mucosa only the p73 gene was significantly less methylated in comparison to tumor mucosa. DNA methylation identified subgroups of diffuse type gastric cancer. Hypermethylation of BRCA1 associated with young age suggests a role in early-onset gastric carcinoma.

DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis

Diffuse type gastric carcinoma is the most aggressive type of gastric cancer. This type of tumor is not preceded by precancerous changes and is associated with early-onset and hereditary syndromes. To test the hypothesis that DNA methylation profile would be useful for molecular classification of the diffuse type gastric carcinoma, DNA methylation patterns of the CpG Island of 17 genes were studied in 104 cases and 47 normal adjacent gastric mucosa by Methylation-specific PCR, Immunohistochemistry and Hierarchicalclustering analysis. The most frequent methylated genes were FHIT, E-cadherin, BRCA1 and APC (>50%),followed by p14, p16, p15, p73, MGMT and SEMA3B (20-49%). Hierarchical clustering analysis reveals four groups with different clinical features. The first was characterized by hypermethylation of BRCA1 and younger age (<45 years old), and the second by hypermethylation of p14 and p16 genes, male predominance and Epstein-Barr virus infection. The third group was characterized by hypermethylation of FHIT and antrum located tumors and the fourth was not associated with any clinical variables. In normal adjacent mucosa only the p73 gene was significantly less methylated in comparison to tumor mucosa. DNA methylation identified subgroups of diffuse type gastric cancer. Hypermethylation of BRCA1 associated with young age suggests a role in early-onset gastric carcinoma.

Epstein-Barr virus-associated primary lymphoepitheliomalike carcinoma of the esophagus.

Primary lymphoepitheliomalike carcinomas (LELC) of the esophagus are uncommon, with only 29 previously reported cases in the literature. Primary LELC of the esophagus is associated with Epstein-Barr virus (EBV). We herein report a 52-year-old man who presented with dysphagia and weight loss and was found to have a polypoid mass in the middle esophagus. Pathologic examination showed LELC. EBV infection was demonstrated by immunohistochemical detection of EBNA-1 in neoplastic cells and polymerase chain reaction amplification for EBNA-3C, BamHI-F, and W1/I1 regions but not by in situ hybridization by EBER-1 transcripts. EBV genotyping analysis demonstrated infection by a novel type "i"/XhoI loss recombinant strain. Although it is accepted that polymorphisms at BamHI-W1/I1 region cosegregate with polymorphisms at XhoI restriction site, this novel recombinant EBV has been identified in healthy donors and in nasal NK/T-cell lymphoma. To our knowledge, this is the first report that describes this recombinant type "i"/XhoI loss EBV strain in a primary LELC of the esophagus.