Fear of COVID-19 scale: validation in Spanish in the Mexican general population.

INTRODUCTION: The fear of COVID-19 scale (FCV-19S) is used to screen for symptoms of anxiety and depression related to COVID-19 in the general population; it consists of seven questions with Likert-type answers (1-5). Our objective was to validate FCV-19S Spanish version in the Mexican general population. MATERIAL AND METHODS: Analytical, cross-sectional design. Three-hundred and six subjects from the general population were included during 2020 after having signed informed consent. Barlett and Kaiser-Meyer-Olkin (KMO) sphericity tests were applied. Reliability was calculated with Cronbach's alpha, and external validity, using the Hospital Anxiety and Depression Scale and Pearson's correlation coefficient for retest. RESULTS: The general population sample included 306 participants; 64.4 % were women (n = 197), mean age was 32 years (18-68). We obtained a KMO = 0.848, internal consistency with Cronbach's alpha = 0.870 (95% CI: 0.848-0.891), a rho coefficient of 0.508 (p < 0.001) and external validity of 0.151 (p = 0.008). Confirmatory analysis showed: χ2 = 22.802 (df = 13) with CMIN-DF = 1.900 (p ≤ 0.001), GFI = 0.972, CFI = 0.901, RMSEA = 0.062 (90% CI: 0.019-0.100) and TLI = 0.827. CONCLUSIONS: According to our findings, the scale shows adequate psychometric properties: reliability, internal consistency, correlation with subsequent measurements and convergence validity, for initial screening of the Mexican general population.

INTRODUCCIÓN: La Escala de temor a la COVID-19 (FCV-19S) se usa en el tamizaje de síntomas de ansiedad y depresión relacionados con la COVID-19 en población general; consta de siete preguntas con respuestas tipo Likert (1-5). Nuestro objetivo fue validar la versión del FCV-19S en la población general mexicana. MATERIAL Y MÉTODOS: Diseño transversal analítico. Se incluyeron 306 sujetos de la población general durante 2020 con firma previa de consentimiento informado. Se aplicaron pruebas de esfericidad de Barlett y Kaiser-Meyer-Olkin (KMO). Se calculó la confiabilidad con el alfa de Cronbach, la validez externa utilizando la Escala hospitalaria de ansiedad y depresión y el coeficiente de correlación de Pearson para retest. RESULTADOS: La muestra de la población general incluyó a 306 participantes, el 64.4% mujeres (n = 197), edad media 32 años (18-68). Obtuvimos un KMO = 0.848, consistencia interna con alfa de Cronbach = 0.870 (IC 95%: 0.848-0.891), coeficiente rho de 0.508 (p < 0.001) y validez externa de 0.151 (p = 0.008). El análisis confirmatorio mostró: χ2 = 22.802 (df = 13) con CMIN-DF= 1.900, p ≤ 0.001, GFI = 0.972, CFI = 0.901, RMSEA = 0.062 (IC 90%: 0.019-0.100) y TLI = 0.827. CONCLUSIONES: La FCV-19S demuestra propiedades psicométricas adecuadas (confiabilidad, consistencia interna, correlación con mediciones subsecuentes y validez de convergencia) para su aplicación en la población general mexicana.

Incidencia de endofugas en pacientes con aneurismas de aorta abdominal infrarrenal intervenidos con técnica endovascular / Incidence of endoleaks in patients with infrarenal abdominal aortic aneurysms treated on with the endovascular technique

Introducción: Las endofugas son la complicación más frecuente de los tratamientos endovasculares de aneurismas de aorta abdominal y torácica. El objetivo de este estudio es describir la frecuencia de endofugas en pacientes con aneurismas de aorta infrarrenal tratados con técnicas endovasculares. Metodología: Estudio de cohorte retrospectivo en el que se incluyeron pacientes con aneurismas infrarrenales tratados con terapia endovascular en dos instituciones de alta complejidad entre el 1 de septiembre de 2013 y el 1 de marzo de 2021. Se incluyeron datos demográficos, antecedentes, características morfológicas del cuello y saco del aneurisma, tipo de prótesis utilizada, presencia y tipo de endofuga. Se realizó un análisis descriptivo univariado. Los intervalos de confianza se describieron con un 95%. Resultados: Se incluyeron 99 pacientes, la media de edad fue 74,37 años, la media de la longitud del cuello fue de 29,47 mm, el 90,24% tuvieron una longitud favorable (>15mm). La media del ángulo fue de 44,57°, el 67,86% tenía un ángulo favorable (<60°). El 28,28% de los pacientes presentaron endofugas, la frecuencia de las endofugas tipo Ia fue de 7,07%, las de tipo Ib 8,08%, las de tipo II 18,37%, las de tipo IIIa y IIIb 1,01%. No se presentaron endofugas tipo IV ni V. Conclusiones: La frecuencia de presentación de endofugas fue del 28,28%; la endofuga más frecuente es la de tipo II 18,37%, ligeramente inferior a lo descrito en la literatura.

Introduction: Endoleaks are the most common complication of endovascular treatment of abdominal and thoracic aortic aneurysms.. The objective of this study is to describe the frequency of endoleaks in patients with infrarenal aortic aneurysms treated with endovascular techniques. Methodology: Retrospective cohort study that included patients from September 1, 2013, to March 1, 2021, with infrarenal aneurysms treated with endovascular therapy at the FOSCAL and FOSCAL international clinics. Demographic data, history, morphological characteristics of the aneurysm neck and sac, type of prosthesis used, presence, and type of endoleak were included. A univariate descriptive analysis was performed. Confidence intervals were reported at 95%. Results: 99 patients were included, the mean age was 74.37 years, the mean neck length was 29.47 mm, 90.24% had a favorable length (>15 mm); The mean angle was 44.57, 67.86% had a favorable angle (<60º). 28.28% of the patients presented endoleaks, the frequency of type Ia endoleaks was 7.07%, type Ib endoleaks 8.08%, type II 18.37%, type IIIa, and IIIb endoleaks 1, 01%. There were no type IV or type V endoleaks. Conclusions: The frequency of presentation of endoleaks was 28.28%; the most frequent endoleak is type II 18.37%. slightly lower than that reported in the literature

Causal Association of Haptoglobin With Obesity in Mexican Children: A Mendelian Randomization Study.

CONTEXT: Little is known about the association between haptoglobin level and cardiometabolic traits. A previous genome-wide association study identified rs2000999 in the HP gene as the stronger genetic contributor to serum haptoglobin level in European populations. OBJECTIVE AND DESIGN: We investigated the association of HP rs2000999 with serum haptoglobin and childhood and adult obesity in up to 540/697 and 592/691 Mexican cases and controls, respectively. Anthropometric and biochemical data were collected. Serum haptoglobin was measured by an immunoturbidimetry assay. HP rs2000999 was genotyped using the TaqMan technology. Mendelian randomization analysis was performed using the Wald and inverse variance weighting methods. RESULTS: Haptoglobin level was positively associated with childhood and adult obesity. HP rs2000999 G allele was positively associated with haptoglobin level in children and adults. HP rs2000999 G allele was positively associated with childhood but not adult obesity. The association between HP rs2000999 and childhood obesity was removed after adjusting for haptoglobin level. In a Mendelian randomization analysis, haptoglobin level genetically predicted by HP rs2000999 showed a significant causal effect on childhood obesity by the Wald and inverse variance weighting methods. CONCLUSION: Our data provide evidence for the first time for a causal positive association between serum haptoglobin level and childhood obesity in the Mexican population. Our study contributes to the genetic elucidation of childhood obesity and proposes haptoglobin as an important biomarker and treatment target for obesity.

[Prevalencia de complicaciones de la diabetes y comorbilidades asociadas en medicina familiar del Instituto Mexicano del Seguro Social].

Introduction: The prevalence of chronic complications and comorbidities in patients with type 2 diabetes (T2D) has increased worldwide. Objective: To compare the prevalence of complications and chronic comorbidities in patients with T2D at 36 family medicine units of five chapters of the Mexican Institute of Social Security (IMSS). Method: Complications (hypoglycemia, diabetic foot, kidney disease, retinopathy, ischemic heart disease, cerebrovascular disease and heart failure) and comorbidities (liver disease, cancer and anemia) were identified according to codes of the International Classification of Diseases, 10th Revision. Comparisons were made by chapter, age, gender and evolution time. Results: Complications and comorbidities were more common in subjects aged ≥ 62 years. Out of 297 100 patients, 34.9 % had any complication; microvascular complications (32 %) prevailed in the industrial North, whereas macrovascular complications (12.3 %) did in the rural East, and comorbidities (5 %) in southern Mexico City. Complications predominated in men (any complication, 30.2 %). Heart failure and comorbidities were more common in women (5.6 % and 4.9 %, respectively). Conclusions: T2D complications and comorbidities showed geographic and gender differences, and were greater with older age and longer evolution time. It is urgent for strategies for the prevention of complications and comorbidities to be reinforced in patients with T2D.

Introducción: La prevalencia de complicaciones crónicas y comorbilidades en pacientes con diabetes tipo 2 (DT2) se han incrementado en el mundo. Objetivo: Comparar la prevalencia de complicaciones y comorbilidades crónicas en pacientes con DT2 en 36 unidades de medicina familiar de cinco delegaciones del Instituto Mexicano del Seguro Social (IMSS). Métodos: Conforme los códigos de la Décima Revisión de la Clasificación Internacional de Enfermedades se identificaron las complicaciones (hipoglucemia, pie diabético, enfermedad renal, retinopatía, enfermedad cardiaca isquémica, enfermedad cerebrovascular y falla cardiaca) y comorbilidades (enfermedad hepática, cáncer, anemia) de DT2. Se compararon por delegación, edad, sexo y tiempo de evolución. Resultados: Las complicaciones y comorbilidades fueron más comunes en personas ≥ 62 años. De 297 100 pacientes, 34.9 % presentó cualquier complicación; microvasculares en el norte industrial (32 %), macrovasculares en el este rural (12.3 %) y comorbilidades (5 %) en el sur de la Ciudad de México; estas complicaciones predominaron en los hombres (cualquier complicación 30.2 %). La falla cardiaca y las comorbilidades fueron más comunes en mujeres (5.6 y 4.9 %). Conclusiones: Las complicaciones y comorbilidades de DT2 mostraron diferencias geográficas y de sexo y fueron mayores con la edad y el tiempo de evolución. Urge reforzar estrategias para la prevención de las complicaciones y comorbilidades en los pacientes con DT2.

Prevalencia de complicaciones de la diabetes y comorbilidades asociadas en medicina familiar del Instituto Mexicano del Seguro Social / Prevalence of complications of diabetes and associated comorbidities in family medicine of the Mexican Institute

Resumen Introducción: La prevalencia de complicaciones crónicas y comorbilidades en pacientes con diabetes tipo 2 (DT2) se han incrementado en el mundo. Objetivo: Comparar la prevalencia de complicaciones y comorbilidades crónicas en pacientes con DT2 en 36 unidades de medicina familiar de cinco delegaciones del Instituto Mexicano del Seguro Social (IMSS). Métodos: Conforme los códigos de la Décima Revisión de la Clasificación Internacional de Enfermedades se identificaron las complicaciones (hipoglucemia, pie diabético, enfermedad renal, retinopatía, enfermedad cardiaca isquémica, enfermedad cerebrovascular y falla cardiaca) y comorbilidades (enfermedad hepática, cáncer, anemia) de DT2. Se compararon por delegación, edad, sexo y tiempo de evolución. Resultados: Las complicaciones y comorbilidades fueron más comunes en personas ≥ 62 años. De 297 100 pacientes, 34.9 % presentó cualquier complicación; microvasculares en el norte industrial (32 %), macrovasculares en el este rural (12.3 %) y comorbilidades (5 %) en el sur de la Ciudad de México; estas complicaciones predominaron en los hombres (cualquier complicación 30.2 %). La falla cardiaca y las comorbilidades fueron más comunes en mujeres (5.6 y 4.9 %). Conclusiones: Las complicaciones y comorbilidades de DT2 mostraron diferencias geográficas y de sexo y fueron mayores con la edad y el tiempo de evolución. Urge reforzar estrategias para la prevención de las complicaciones y comorbilidades en los pacientes con DT2.

Abstract Introduction: The prevalence of chronic complications and comorbidities in patients with type 2 diabetes (T2D) has increased worldwide. Objective: To compare the prevalence of complications and chronic comorbidities in patients with T2D at 36 family medicine units of five chapters of the Mexican Institute of Social Security (IMSS). Method: Complications (hypoglycemia, diabetic foot, kidney disease, retinopathy, ischemic heart disease, cerebrovascular disease and heart failure) and comorbidities (liver disease, cancer and anemia) were identified according to codes of the International Classification of Diseases, 10th Revision. Comparisons were made by chapter, age, gender and evolution time. Results: Complications and comorbidities were more common in subjects aged ≥ 62 years. Out of 297 100 patients, 34.9 % had any complication; microvascular complications (32 %) prevailed in the industrial North, whereas macrovascular complications (12.3 %) did in the rural East, and comorbidities (5 %) in southern Mexico City. Complications predominated in men (any complication, 30.2 %). Heart failure and comorbidities were more common in women (5.6 % and 4.9 %, respectively). Conclusions: T2D complications and comorbidities showed geographic and gender differences, and were greater with older age and longer evolution time. It is urgent for strategies for the prevention of complications and comorbidities to be reinforced in patients with T2D.

Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin.

Epidemiological studies have shown that most cases of lung cancers (85%-90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known about the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here, we show that lung cancer patients with a smoking history have low E-cadherin levels and loss of E-cadherin is a poor prognostic factor in smokers. Moreover, the downregulation of E-cadherin correlates with the number of pack years. In an attempt to determine the role of long-term cigarette smoking on EMT, we observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers, including E-cadherin and upregulation of mesenchymal markers. CSC decreases E-cadherin expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadherin expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadherin promoter is important for CSC-mediated downregulation of E-cadherin. The histone deacetylase (HDAC) inhibitor MS-275 reverses CSC-induced EMT, migration, and invasion through the restoration of E-cadherin expression. These results suggest that recruitment of HDACs by transcriptional repressors LEF-1 and Slug is responsible for E-cadherin suppression and EMT in cigarette smokers and provide a potential drug target toward the treatment of lung cancer.

In-depth proteomic analysis of nonsmall cell lung cancer to discover molecular targets and candidate biomarkers.

Advances in proteomic analysis of human samples are driving critical aspects of biomarker discovery and the identification of molecular pathways involved in disease etiology. Toward that end, in this report we are the first to use a standardized shotgun proteomic analysis method for in-depth tissue protein profiling of the two major subtypes of nonsmall cell lung cancer and normal lung tissues. We identified 3621 proteins from the analysis of pooled human samples of squamous cell carcinoma, adenocarcinoma, and control specimens. In addition to proteins previously shown to be implicated in lung cancer, we have identified new pathways and multiple new differentially expressed proteins of potential interest as therapeutic targets or diagnostic biomarkers, including some that were not identified by transcriptome profiling. Up-regulation of these proteins was confirmed by multiple reaction monitoring mass spectrometry. A subset of these proteins was found to be detectable and differentially present in the peripheral blood of cases and matched controls. Label-free shotgun proteomic analysis allows definition of lung tumor proteomes, identification of biomarker candidates, and potential targets for therapy.

Nuclear p63 expression in osteoblastic tumors.

Expression of the p63 tumor suppressor protein has been reported in the mononuclear stromal cells of giant cell tumor of the bone, which may represent osteoblast-precursor cells. Only a limited number of osteoblastic tumors have been studied for p63 expression thus far. We therefore examined whether p63 may serve as a marker for osteoblastic differentiation in osteosarcomas or as a differential diagnostic marker to distinguish osteoblastoma from osteosarcoma. Immunohistochemical stains for p63 were performed on a tissue microarray containing 71 chemotherapy naïve biopsy samples of osteosarcoma, 21 whole sections of osteosarcoma, and 8 osteoblastomas. Nuclear p63 was detected in seven of eight osteoblastomas but was restricted to stromal cells within primitive, immature-appearing areas of osteoid deposition. Although only 7 of 71 (10 %) biopsy samples of osteosarcoma represented on the tissue microarray were positive for p63, 7 of 21 (33 %) osteosarcomas were positive when whole tissue sections were evaluated. Although p63 is detected in most osteoblastomas, it is also observed in a significant subset of osteosarcomas, severely limiting its utility in distinguishing between benign and malignant osteoblastic tumors. The relatively low prevalence of p63 expression in osteosarcoma would also seem to preclude its use as a marker of osteoblastic differentiation in skeletal sarcomas.

Smoking attenuates transforming growth factor-ß-mediated tumor suppression function through downregulation of Smad3 in lung cancer.

Epidemiologic studies have shown that most cases of lung cancers (85%-90%) are directly attributable to cigarette smoking. Although much information has been gained about the effects of cigarette smoking on various signaling pathways causing lung cancer, nothing is known about the effect of cigarette smoking on the TGF-ß-induced tumor suppressor function in lung cancer. To address this issue, lung adenocarcinoma A549 and immortalized bronchial epithelial HPL1A cells were chronically treated with cigarette smoke condensate (CSC) and dimethyl sulfoxide (as a control) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-ß-mediated transcription due to reduced expression of Smad3. Long-term CSC treatment reduced apoptosis, increased cell viability, decreased TGF-ß-mediated growth inhibition, and enhanced tumorigenicity. The decrease in apoptosis is due to the upregulation of Bcl-2, which is a downstream target of Smad3. Re-expression of Smad3 in the CSC-treated cells restored TGF-ß signaling, increased apoptosis, and decreased cell viability and tumorigenicity. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability, and increased TGF-ß-mediated growth inhibition. Expression of Smad3 is lower in lung tumors of current smokers than that observed in never-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-ß-mediated growth inhibition and apoptosis by reducing expression of Smad3.

Loss of polymeric immunoglobulin receptor expression is associated with lung tumourigenesis.

Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis. pIgR expression was evaluated by immunohistochemistry in airways of patients with normal mucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression. Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues. pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation.

Occasional staining for p63 in malignant vascular tumors: a potential diagnostic pitfall.

Expression of p63, a putative marker for epithelial or myoepithelial differentiation, has been used to distinguish spindle cell carcinoma from sarcoma. The specificity of p63 for epithelial differentiation has not been thoroughly evaluated however, since p63 expression has been explored in only a handful of mesenchymal tumors. After observing unexpected immunohistochemical staining for p63 in an angiosarcoma of the breast, we evaluated a series of benign and malignant vascular tumors to determine the frequency of such a finding. Nuclear immunoreactivity to p63 was detected, at least focally, in 24% of malignant vascular tumors other than Kaposi sarcoma, which was uniformly negative. Benign vascular tumors were also negative for p63. Although p63 expression in tumors of vascular differentiation is unusual, it may be seen occasionally in some malignant vascular tumors. Thus, p63 is not entirely specific for epithelial differentiation. Since soft tissue angiosarcomas and hemangioendotheliomas sometimes express cytokeratins, the finding of nuclear p63 represents another potential pitfall in the differential diagnosis between poorly-differentiated carcinomas and vascular neoplasms.

Expression of focal adhesion kinase in small-cell lung carcinoma.

BACKGROUND: The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase linked to tumor growth, invasion, and metastasis. FAK is overexpressed and associated with prognosis in many cancers, but its prognostic value in small-cell lung carcinoma (SCLC) is unknown and was the focus of this study. METHODS: Total FAK expression was analyzed via immunohistochemistry in tissue microarrays consisting of formalin-fixed, paraffin-embedded SCLC specimens from 85 patients. FAK staining scores were tested for correlations with pathological characteristics and clinical outcomes. Phospho-paxillin was also tested in 35 of the 85 specimens to evaluate whether FAK expression was associated with downstream signaling. RESULTS: Specific FAK expression was localized to the cytoplasm of 78/85 (92%) SCLCs. FAK expression was scored low in 11 (13%), moderate in 17 (20%), and high in 50 (59%) SCLCs. FAK staining scores treated as continuous variables did not correlate with SCLC disease stage, response to therapy, recurrence/progression-free survival, or overall survival. Moreover, total FAK expression did not correlate with phospho-paxillin Tyr(118) expression. CONCLUSIONS: Total FAK is strongly expressed in a majority of SCLC tumors. However, the expression evaluated via immunohistochemistry is not a prognostic factor in patients with SCLC.

Osteosarcoma: Differential Diagnostic Considerations.

Accurate diagnosis of bone-forming tumors, including correct subclassification of osteogenic sarcoma is critical for determination of appropriate clinical management and prediction of patient outcome. The morphologic spectrum of osteogenic sarcoma is extensive, however, and its histologic mimics are numerous. This review focuses on the major differential diagnoses of the specific subtypes of osteosarcoma, presents summaries of various diagnoses, and provides tips to overcoming pitfalls in diagnosis.

Lung cancer diagnosis from proteomic analysis of preinvasive lesions.

Early detection may help improve survival from lung cancer. In this study, our goal was to derive and validate a signature from the proteomic analysis of bronchial lesions that could predict the diagnosis of lung cancer. Using previously published studies of bronchial tissues, we selected a signature of nine matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) mass-to-charge ratio features to build a prediction model diagnostic of lung cancer. The model was based on MALDI MS signal intensity (MALDI score) from bronchial tissue specimens from our 2005 published cohort of 51 patients. The performance of the prediction model in identifying lung cancer was tested in an independent cohort of bronchial specimens from 60 patients. The probability of having lung cancer based on the proteomic analysis of the bronchial specimens was characterized by an area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88) in this validation cohort. Eight of the nine features were identified and validated by Western blotting and immunohistochemistry. These results show that proteomic analysis of endobronchial lesions may facilitate the diagnosis of lung cancer and the monitoring of high-risk individuals for lung cancer in surveillance and chemoprevention trials.

Role of STRAP in regulating GSK3ß function and Notch3 stabilization.

Glycogen synthase kinase 3ß (GSK3ß) can regulate a broad range of cellular processes in a variety of cell types and tissues through its ability to phosphorylate its substrates in a cell- and time-specific manner. Although it is known that Axin and presenilin help to recruit ß-catenin/Smad3 and tau protein to GSK3ß, respectively, it is not clear how many of the other GSK3ß substrates are recruited to it. Here, we have established the binding of GSK3ß with a novel scaffold protein, STRAP, through its WD40 domains. In a new finding, we have observed that STRAP, GSK3ß and Axin form a ternary complex together. We show for the first time that intracellular fragment of Notch3 (ICN3) binds with GSK3ß through the ankyrin repeat domain. This binding between STRAP and GSK3ß is reduced by small-molecule inhibitors of GSK3ß. Further studies revealed that STRAP also binds ICN3 through the ankyrin repeat region, and this binding is enhanced in a proteasomal inhibition-dependent manner. In vivo ubiquitination studies indicate that STRAP reduces ubiquitination of ICN3, suggesting a role of STRAP in stabilizing ICN3. This is supported by the fact that STRAP and Notch3 are co-upregulated and co-localized in 59% of non-small cell lung cancers, as observed in an immunohistochemical staining of tissue microarrays. These results provide a potential mechanism by which STRAP regulates GSK3ß function and Notch3 stabilization and further support the oncogenic functions of STRAP.

Transarticular spread of Ewing sarcoma mimicking septic arthritis.

Transarticular spread of tumor is rare; it has only been reported in the sacroiliac joint, intervertebral disk spaces, and facet joints. The anatomic and kinetic characteristics of the sacroiliac joint, as well as the changes the joint undergoes during a lifetime, make it particularly vulnerable to transarticular tumor invasion. Although extremely rare, Ewing sarcoma can extend through the sacroiliac joint and be virtually indistinguishable radiologically from septic arthritis. Furthermore, the clinical presentation of a child with Ewing sarcoma can be similar to that of a child with osteomyelitis. Laboratory values are quite nonspecific and are not always helpful in differentiating between the entities. Therefore, the possibility of sacroiliac joint transarticular Ewing sarcoma should be considered in a child presenting with hip pain, despite clinical, radiological and laboratory findings suggesting an infectious process.

Peroxisome proliferator-activated receptor beta/delta expression and activation in lung cancer.

Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a ligand-binding inducible transcriptional factor linked to carcinogenesis. Important functions of PPARbeta/delta were demonstrated in series of human epithelial cancers; however, its role in lung cancer remains controversial. We investigated the differential expression level and localization of PPARbeta/delta in tumors and adjacent normal lung tissue, and the effect of PPARbeta/delta activation on lung cancer cell proliferation and apoptosis. PPARbeta/delta was expressed in all studied human non-small cell lung cancers, and strong PPARbeta/delta immunoreactivity was observed in epithelial cells of more than 75% of studied lung tumors. PPARbeta/delta expression was consistently limited to the cancer cells in tumor tissue, while in adjacent normal lung tissue it was limited predominantly to the mononuclear cells. We found that ligand-binding activation of PPARbeta/delta stimulates cell proliferation (an effect that was blocked by a dominant-negative construct of PPARbeta/delta), stimulates anchorage-independent cell growth, and inhibits apoptosis in lung cancer cell lines. Importantly, the activation of PPARbeta/delta induces Akt phosphorylation correlated with up-regulation of PDK1, down-regulation of PTEN, and increased expression of Bcl-xL and COX-2. These findings indicate that PPARbeta/delta exerts proliferative and anti-apoptotic effects via PI3K/Akt1 and COX-2 pathways. In conclusion, PPARbeta/delta is strongly expressed in the majority of lung cancers, and its activation induces proliferative and survival response in non-small cell lung cancer.

MALDI-MS derived prognostic protein markers for resected non-small cell lung cancer.

Protein signals obtained directly from frozen lung tissue sections using MALDI-MS were used to predict nodal involvement and survival in resected non-small cell lung cancer (NSCLC). We have identified a list of these protein signals and further evaluated their prognostic values for NSCLC using immunohistochemistry (IHC). Kaplan-Meier analysis was used to assess the mortality risk associated with the prognostic protein IHC-staining intensities. The combined IHC scores of calmodulin, thymosin ß4, and thymosin ß10 were found to be correlated with NSCLC patient survival (p = 0.004). Furthermore, low cofilin-1 IHC-staining intensity was found to be correlated with a better outcome for patients with negative lymph node status (p = 0.006) while high cofilin-1 IHC-staining intensity was found to be correlated with a better outcome for patients with positive node status (p = 0.034). In conclusion, the prognostic protein signals selected using MALDI-MS can be identified and tested by IHC in formalin-fixed tissue samples. MALDI-MS-derived protein signals can be potentially translated to a conventional clinical setting to aid in the prognosis of patients with NSCLC at the molecular level.

Diagnostic accuracy of MALDI mass spectrometric analysis of unfractionated serum in lung cancer.

PURPOSE: There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls. PATIENTS AND METHODS: We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training-testing paradigm with application of the model profile defined in a training set to a blinded test cohort. RESULTS: Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A. CONCLUSIONS: We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.

Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis.

The development and progression of malignancies is a complex multistage process that involves the contribution of a number of genes giving growth advantage to cells when transformed. The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex with tumor-suppressor or prooncogenic activities depending on the cell type and the stage of the disease. We have previously reported the identification of a novel WD-domain protein, STRAP, that associates with both TGF-beta receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-beta-induced transcription. Here, we show that STRAP is ubiquitously expressed and is localized in both cytoplasm and nucleus. STRAP is up-regulated in 60% colon and in 78% lung carcinomas. Stable expression of STRAP results in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and in down-regulation of the cyclin-dependent kinase inhibitor p21(Cip1), which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-beta-mediated transcription, and growth inhibition are induced in STRAP-knockout mouse embryonic fibroblasts compared with wild-type cells. Ectopic expression of STRAP in A549 lung adenocarcinoma cell line inhibits TGF-beta-induced growth inhibition and enhances anchorage-independent growth of these cells. Moreover, overexpression of STRAP increases tumorigenicity in athymic nude mice. Knockdown of endogenous STRAP by small interfering RNA increases TGF-beta signaling, reduces ERK activity, increases p21(Cip1) expression, and decreases tumorigenicity. Taken together, these results suggest that up-regulation of STRAP in human cancers may provide growth advantage to tumor cells via TGF-beta-dependent and TGF-beta-independent mechanisms, thus demonstrating the oncogenic function of STRAP.