Modulation in the expression levels and protein localization of cell volume and actin cytoskeleton associated proteins by the Slit/ Robo signaling pathway in Glioblastoma multiforme.

Honorable Mention Winner Glioblastoma multiforme (GBM) is the most aggressive and malignant primary brain tumor in adults1. Even after surgical resection, chemotherapy, and radiation, the average patient survival rate is 14 months2. Recent studies indicate that GBM tumors that contact the lateral ventricles within the subventricular zone (SVZ) tend to migrate and recur at distal locations after surgical resection3. One important signaling pathway in Neural Progenitor Cells (NPCs) migration from the SVZ to the olfactory bulbs is the Slit/Robo signaling pathway4. Slit2 proteins are produced by the choroid plexus and create a gradient across ependymal cells. Slit2 proteins then interact with the Roundabout (Robo) receptor on NPCs and acts as a chemo-repelling agent5. This Slit2/ Robo1 signaling pathway is a possible mechanism that contributes to GBM migration from the SVZ to distal locations. The intracellular changes when the Slit/Robo pathway is activated includes changes in cell volume regulation and actin cytoskeleton dynamics6. We then examined how the Slit2/ Robo1 signaling pathway causes changes in the expression of cell volume regulatory genes (AQP4, KCC1, NKCC1, NCC), actin cytoskeleton genes regulatory genes (p-ERM, p-Cofilin), and the localization of actin-associated proteins (FAK, Paxillin, N-WASP, Vinculin). It was found that the Slit/Robo signaling pathway increases the expression levels of genes that contribute to cell volume regulation in GBM cells, and the Slit/Robo signaling pathway increases the phosphorylation of p-Cofilin and p-ERM. This indicates that the Slit2/ Robo1 pathway participates in the regulation of cell volume and actin cytoskeleton dynamics in GBM cells

New four-dimensional integrals by Mellin-Barnes transform

This paper is devoted to the calculation by Mellin-Barnes transform of a especial class of integrals. It contains double integrals in the position space in d = 4-2e dimensions, where e is parameter of dimensional regularization. These integrals contribute to the effective action of the N = 4 supersymmetric Yang-Mills theory. The integrand is a fraction in which the numerator is a logarithm of ratio of spacetime intervals, and the denominator is the product of powers of spacetime intervals. According to the method developed in the previous papers, in order to make use of the uniqueness technique for one of two integrations, we shift exponents in powers in the denominator of integrands by some multiples of e. As the next step, the second integration in the position space is done by Mellin-Barnes transform. For normalizing procedure, we reproduce first the known result obtained earlier by Gegenbauer polynomial technique. Then, we make another shift of exponents in powers in the denominator to create the logarithm in the numerator as the derivative with respect to the shift parameter delta. We show that the technique of work with the contour of the integral modified in this way by using Mellin-Barnes transform repeats the technique of work with the contour of the integral without such a modification. In particular, all the operations with a shift of contour of integration over complex variables of two-fold Mellin-Barnes transform are the same as before the delta modification of indices, and even the poles of residues coincide. This confirms the observation made in the previous papers that in the position space all the Green function of N = 4 supersymmetric Yang-Mills theory can be expressed in terms of UD functions.Comment: Talk at El Congreso de Matematica Capricornio, COMCA 2009, Antofagasta, Chile and at DMFA seminar, UCSC, Concepcion, Chile, 24 pages; revised version, Introduction is modified, Conclusion is added, five Appendices are added, Appendix E is ne

Determining glioblastoma proteome changes in response to lateral ventricle neural stem cells

Glioblastoma (GBM) is the most common and malignant primary tumor in adults. When GBM tumors are located close to the lateral ventricle they display a more aggressive recurrence pattern and negatively impact patient survival. These findings suggest the involvement of the subventricular zone neurogenic niche in GBM malignancy. To define the inter-cellular communication between neural stem cells and GBM cells, we optimized a tool to determine cell-specific proteomic changes of GBM cells in response to neural stem cell proximity. We cloned the mutated methionyl-tRNA synthetase (MetRS) gene into the lentiviral plasmid MetRS puro. MetRS allows for incorporation of azide-tagged methionine analog azidonorleucine (ANL) into newly formed proteins, effectively labeling proteins synthesized by expressing cells. We utilized the pLKO.1 vector backbone allowing puromycin resistance as a selection method. The MetRS L274 modification was confirmed, as only MetRS-transduced cells of both commercial HEK and primary GBM1A cell lines selectively incorporated ANL. Following verification, we successfully packaged the plasmid into a lentivirus. We transduced primary human fetal neural stem cell (hfNSC) and GBM lines and selected the MetRS-expressing cells by puromycin exposure. After 96 hours, wild type (WT) cells died while successfully transduced cells exhibited resistance and the ANL-compatible MetRS enzyme. Co-cultures consisting of MetRS-transduced GBM and WT hfNSCs were used to simulate a similar environment of glioblastoma neighboring lateral ventricles. Proteome Profiler results showed a significant downregulation of an angiogenesis inhibitor and upregulation of malignancy promoting proteins in GBM1A. Going forward, this analysis method will be used for cell-specific proteomics in vivo

Morbimortalidad de las enfermedades cardiovasculares: causas, pruebas diagnósticas y prevención.

Cardiovascular diseases represent an important cause of morbidity and mortality in the world population. The incidence and prevalence of these pathologies have increased significantly in recent years and are expected to continue to rise due to risk factors such as arterial hypertension, sedentary lifestyle, smoking, and diabetes mellitus, among others. The objective of the research was to describe the morbidity and mortality of cardiovascular diseases: causes, diagnostic tests, and prevention in the general population. An exploratory document review design was used to analyze information from different studies. The results indicated that cardiovascular diseases affect men and women differently in different regions of the world, and that men have a higher mortality rate compared to women. It was highlighted that the main causes of these diseases are high blood pressure, smoking, obesity, diabetes, dyslipidemia and sedentary lifestyle. The main diagnostic tests were C-reactive protein, cardiac troponins and natriuretic peptides. It is concluded that cardiovascular disease remains an important cause of morbidity and mortality worldwide, especially in men. Therefore, it is important to take preventive measures to reduce the risk of cardiovascular diseases such as a balanced diet, reducing tobacco and alcohol, not being sedentary and physical exercise.  Las enfermedades cardiovasculares representan una causa importante de morbimortalidad en la población mundial. La incidencia y prevalencia de estas patologías han aumentado significativamente en los últimos años, y se espera que continúen en ascenso debido a factores de riesgo como la hipertensión arterial, el sedentarismo, el tabaquismo y la diabetes mellitus, entre otros. El objetivo de la investigación fue describir la morbimortalidad de las enfermedades cardiovasculares: causas, pruebas diagnósticas y prevención en población general. Se utilizó un diseño de revisión documental de tipo exploratorio para analizar la información de diferentes estudios. Los resultados indicaron que las enfermedades cardiovasculares afectan de manera diferente a hombres y mujeres en diferentes regiones del mundo, y que los hombres tienen una tasa de mortalidad más alta en comparación con las mujeres. Se destacó que las principales causas de estas enfermedades son la hipertensión arterial, el tabaquismo, la obesidad, la diabetes, la dislipidemia y el sedentarismo. Las pruebas de diagnóstico principales fueron proteína C reactiva, troponinas cardíacas y péptidos natriuréticos. Se concluye que las enfermedades cardiovasculares siguen siendo una importante causa de morbilidad y mortalidad en todo el mundo, especialmente en los hombres. Por eso es importante tomar medidas preventivas para reducir el riesgo de enfermedades cardiovasculares como una dieta balanceada, disminuir el tabaco y alcohol, no sedentarismo y ejercicio físico

Editorial: Neural Stem Cells of the Subventricular Zone: From Neurogenesis to Glioblastoma Origin

EM is funded by VI Plan Propio de Investigación (Universidad de Sevilla) Grant number 2020/0000081. NZ and HG-C are funded by the NIH-NINDS K01NS110930-03 and the Neuro oncology convergence. CC is funded by the Integrated Territorial Investment Operational Programme of the European Commission and by the Department of Department of Health and Families (Consejerıa de Salud y Familias) of the Regional Government of Andalusia. Project reference: ITI-0042-2019: ITI Cadiz 2019Ye

Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential

Abstract Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival

Prevalencia de anemia moderada a severa en pacientes con enfermedad renal crónica en hemodiálisis

Introducción: Un hallazgo frecuente en la enfermedadrenal crónica es la anemia, debido principalmente aldéficit en la producción de eritropoyetina. Otros factorescomo el déficit de hierro, de vitamina B12 y de ácido fólicopueden intervenir en su fisiopatología. Un gran porcentajede los pacientes con enfermedad renal crónica que seencuentran en hemodiálisis sufren de anemia, siendonecesario considerar qué otras comorbilidades se puedenasociar a esta manifestación.Materiales y métodos: Se realizó un estudio retrospectivoy descriptivo en 43 pacientes con enfermedad renalcrónica en hemodiálisis que acudieron a la ClínicaMenydial de los Riñones de Riombamba-Ecuador en el año2011. Se examinaron las historias clínicas para recolectarinformación referente a las cifras de hemoglobina paraevaluar la prevalencia de anemia moderada a severa. Serealizó un modelo de regresión logística múltiple ajustadopor: sexo, edad, urea, creatinina, BUN, hiperpotasemiay glicemia. Se consideraron resultados estadísticamentesignificativos cuando p<0,05Resultados: El 53,5% de la población estudiada presentóanemia moderada a severa, siendo más prevalente enmujeres, con un 80% comparado a un 39,3% en loshombres. Se observó que valores elevados de urea, así comolos niveles de BUN mostraron asociación estadísticamentesignificativa con la anemia moderada a severa (χ2=5,58;p=0,018 y χ2=5,43; p=0,020 respectivamente). Lasvariables que mostraron mayor influencia para la anemiafueron el sexo femenino (OR=37,62; IC95%: 2,41-58,51)y la urea elevada (OR=28,73; IC95%: 28,73-45,34).Conclusión: La mitad de la población estudiada presentóanemia moderada a severa, lo cual se considera unaprevalencia elevada, teniendo un impacto negativo en estospacientes ya que es un factor de riesgo para mortalidad.Asimismo, se observó una asociación entre uremia yanemia en enfermos renales crónicos en hemodiálisis, locual implica un riesgo aumentado para mortalidad porenfermedad cardiovascular en estos paciente

Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone

Abstract Background Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and increased incidence of distal tumor recurrence. This may be due in part to interaction of GBM with factors of the subventricular zone (SVZ), including those contained within the cerebrospinal fluid (CSF). However, direct interaction of GBM tumors with CSF has not been proved and would be hindered in the presence of an intact ependymal cell layer. Methods Here, we investigate the ependymal cell barrier and its derived extracellular matrix (ECM) fractones in the vicinity of a GBM tumor. Patient-derived GBM cells were orthotopically implanted into immunosuppressed athymic mice in locations distal and proximal to the LV. A PBS vehicle injection in the proximal location was included as a control. At four weeks post-xenograft, brain tissue was examined for alterations in ependymal cell health via immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. Results We identified local invading GBM cells within the LV wall and increased influx of CSF into the LV-proximal GBM tumor bulk compared to controls. In addition to the physical disruption of the ependymal cell barrier, we also identified increased signs of compromised ependymal cell health in LV-proximal tumor-bearing mice. These signs include increased accumulation of lipid droplets, decreased cilia length and number, and decreased expression of cell channel proteins. We additionally identified elevated numbers of small fractones in the SVZ within this group, suggesting increased indirect CSF-contained molecule signaling to tumor cells. Conclusions Our data is the first to show that LV-proximal GBMs physically disrupt the ependymal cell barrier in animal models, resulting in disruptions in ependymal cell biology and increased CSF interaction with the tumor bulk. These findings point to ependymal cell health and CSF-contained molecules as potential axes for therapeutic targeting in the treatment of GBM

Lupus eritematoso sistémico con presentación cutánea: reporte de caso clínico

El Lupus Eritematoso Sistémico (LES) es una enfermedadinflamatoria, autoinmune y crónica que afecta a múltiplesórganos mediante la producción de autoanticuerpos y complejosinmunitarios, causando síntomas de acuerdo a su localización,pudiendo ser leves, graves, e incluso fulminantes.Su manifestación cutánea puede presentarse junto a lasmanifestaciones sistémicas, llegando a ser muy intensa, deforma que predomine una extensa necrosis cutánea. Debidoa que no existe un síntoma o hallazgo exclusivo para hacer eldiagnóstico de LES, nos basamos en hallazgos clínicos y delaboratorio. El American College of Rheumatology ha establecidocriterios que se utilizan para confirmar el diagnósticoen pacientes que ingresan para grandes estudios. Su tratamientodepende de las manifestaciones clínicas, su abordajedebe ser multidisciplinario y a pesar de los avances en relacióna ello, su pronóstico continúa siendo grave. El presentecaso clínico se trata de una mujer de 32 años, diagnosticadade LES grave con presentación cutánea subaguda, con buenarespuesta al tratamiento posterior al diagnóstico. Por lotanto es necesario que el médico de atención primaria separeconocer a este tipo de pacientes a fin de realizar un diagnósticotemprano para que sea instaurado un manejo eficazy oportuno en estos pacientes