NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling.

BACKGROUND: mTORC2 is a critical regulator of cytoskeleton organization, cell proliferation, and cancer cell survival. Activated mTORC2 induces maximal activation of Akt by phosphorylation of Ser-473, but regulation of Akt activity and signaling crosstalk upon growth factor stimulation are still unclear. RESULTS: We identified that NUAK1 regulates growth factor-dependent activation of Akt by two mechanisms. NUAK1 interacts with mTORC2 components and regulates mTORC2-dependent activation of Akt by controlling lysosome positioning and mTOR association with this organelle. A second mechanism involves NUAK1 directly phosphorylating Akt at Ser-473. The effect of NUAK1 correlated with a growth factor-dependent activation of specific Akt substrates. NUAK1 induced the Akt-dependent phosphorylation of FOXO1/3a (Thr-24/Thr-32) but not of TSC2 (Thr-1462). According to a subcellular compartmentalization that could explain NUAK1's differential effect on the Akt substrates, we found that NUAK1 is associated with early endosomes but not with plasma membrane, late endosomes, or lysosomes. NUAK1 was required for the Akt/FOXO1/3a axis, regulating p21CIP1, p27KIP1, and FoxM1 expression and cancer cell survival upon EGFR stimulation. Pharmacological inhibition of NUAK1 potentiated the cell death effect induced by Akt or mTOR pharmacological blockage. Analysis of human tissue data revealed that NUAK1 expression positively correlates with EGFR expression and Akt Ser-473 phosphorylation in several human cancers. CONCLUSIONS: Our results showed that NUAK1 kinase controls mTOR subcellular localization and induces Akt phosphorylation, demonstrating that NUAK1 regulates the growth factor-dependent activation of Akt signaling. Therefore, targeting NUAK1, or co-targeting it with Akt or mTOR inhibitors, may be effective in cancers with hyperactivated Akt signaling.

Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival of Tsc2-Null Cells.

Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb's farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.

Global longitudinal strain as a biomarker in diabetic cardiomyopathy. A comparative study with Gal-3 in patients with preserved ejection fraction / Deformación longitudinal global como un biomarcador en miocardiopatía diabética. Estudio comparativo con galectina-3 en pacientes con fracción de eyección preservada

Abstract: Objectives: To establish a relationship between global longitudinal strain (GLS) and Galectin-3 in pre-clinical heart failure in diabetic patients. Galectin-3 is a biomarker in heart failure with depressed ejection fraction (HFdEF). The hypothesis is presented that Galectin-3 is related to GLS and can detect left ventricular dysfunction in heart failure with preserved ejection fraction. Methods: Galectin-3 and GLS were measured in 121 asymptomatic individuals: 14 diabetics with mild depressed ejection fraction (mdEF) (LVEF 47.0 ± 6.9); 76 diabetics with preserved ejection fraction (LVEF 61 ± 5.5), and 31 controls (61.7 ± 5.1). Results: Galectin-3 was elevated in all diabetics vs controls (3.46 ± 1.36 ng/ml vs 2.78 ± 0.91 ng/ml; p = .003). It was also elevated in mdEF (3.76 ± 1.12 ng/ml vs 2.78 ± 0.9 ng/ml; p = .009) and pEF subjects (3.41 ± 1.40 ng/ml vs 2.78 ± 0.9 ng/ml; p = .058), respectively, vs controls. No difference in Gal-3 was found between diabetic groups (p = .603). Diabetics had lower GLS than controls (-18.5 ± 3.9 vs -20 ± 2.6; p = .022). Diabetics with mdEF had lower GLS than those with pEF (-13.3 ± 3.41 vs -19 ± 3.2; P<.001). There was no difference in GLS with pEF compared to controls (-19.4 ± 3.2 vs -20 ± 2.6; p = .70). Conclusions: Galectin-3 is elevated in diabetic patients with mdEF, and is associated with a diminished GLS. GLS could be an early marker of left ventricular dysfunction as well as evidence of diabetic cardiomyopathy.

Resumen: Objetivos: Establecer una asociación entre deformación longitudinal global (DLG) y galectina-3 en insuficiencia cardiaca preclínica en pacientes diabéticos. Galectina-3 es un biomarcador en insuficiencia cardiaca con fracción de eyección deprimida. Nuestra hipótesis es que la DLG y galectina-3 correlacionan y pueden detectar disfunción ventricular en insuficiencia cardiaca con FEVI preservada. Métodos: Se midieron galectina-3 y DLG en 121 individuos asintomáticos: 14 diabéticos con FEVI deprimida leve (FEdl) (FEVI 47 ± 6.9); 76 diabéticos con FEVI preservada (FEp) (FEVI 61 ± 5.5) y 31 sujetos controles (FEVI 61.7 ± 5.1). Resultados: Galectina-3 se encontró elevada en todos los diabéticos vs controles (3.46 ± 1.36 ng/ml vs 2.78 ± 0.91 ng/ml; p = 0.003). Está elevada en sujetos con FEdl (3.76 ± 1.12 vs 2.78 ± 0.9 vs ng/ml p = 0.009) y FEp (3.41 ± 1.40 vs 2.78 ± 0.9 ng/ml p = 0.058), respectivamente vs controles; no encontramos diferencia en galectina-3 en ambos grupos de diabéticos (p = 0.603). Los diabéticos tienen menor DLG que los controles (-18.5 ± 3.9 vs -20 ± 2.6; p = 0.022). Los diabéticos con FEdl tienen DLG más disminuida que aquellos con FEp (-13.3 ± 3.41 vs -19 ± 3.2; p < 0.001). No existe diferencia en DLG con FEp y controles (-19.4 ± 3.2 vs -20 ± 2.6; p = 0.70). Conclusiones: Galectina-3 está elevada en diabéticos con FEdl y correlaciona DLG disminuida. DLG podría ser un marcador temprano de disfunción ventricular y evidencia en miocardiopatía diabética.

Congestive Heart Failure with Preserved Ejection Fraction in a Patient with Light Chain (AL) Amyloidosis and Multiple Myeloma.

BACKGROUND Amyloidosis is characterized by tissue deposition of insoluble fibrillar proteins and it affects almost every organ; there are many types and the heart can be affected in all of them. CASE REPORT Our report describes a middle-aged man who presented to the Emergency Department with congestive heart failure. Clinical, electrocardiographic, and echocardiographic findings suggested the presence of an infiltrative disease, so an abdominal fat tissue biopsy was performed. A final diagnosis of systemic amyloidosis with heart involvement was made. CONCLUSIONS This case highlights the importance of combining clinical, electrocardiographic, and echocardiographic information in the diagnosis of complex diseases like amyloidosis with heart involvement.

Prevalencia del síndrome intestino irritable en la población adulta venezolana / Prevalence of irritable bowel syndrome in venezuelan adults

El síndrome del intestino irritable (SII) es un trastorno digestivo funcional que afecta del 10 al 20% de la población general. Existen pocos estudios en Latinoamérica que muestren su prevalencia nacional, y en Venezuela no disponemos de investigación que reporte tan importante cifra. Estudio multicéntrico, descriptivo, transversal, durante los meses abril y mayo del 2011. Se utilizó el cuestionario validado de la Fundación Roma, con quienes firmamos convenio como Servicio de Gastroenterología del Hospital Vargas de Caracas. Se seleccionaron al azar 15 estados, en cada uno un municipio, y de estos lugares como iglesias, centros comerciales, reuniones de Consejos Comunales, paradas de autobuses, etc. Los valores obtenidos fueron transcritos en una base de datos en Excel y procesados con EPIDAT 3.1. De 1781 personas encuestadas, 299 presentaron criterios clínicos diagnósticos para SII de acuerdo a Roma III. La prevalencia nacional del SII fue de 16,80%, correspondiendo 81,6% a mujeres (244) y 18,4% a hombres (55). El grupo etario entre 38 y 47 años fue el más afectado (26,43%) y el subtipo mixto el más predominante. La prevalencia del SII en la población adulta venezolana según los criterios de Roma III es de 16,80%

Irritable bowel syndrome (IBS) is a functional digestive disorder that affects 10 to 20% of the general population. Few studies exist in Latin America that shows the national prevalence, and in Venezuela we don´t have investigation resources that support those numbers. Multicenter study, descriptive, transversal, during the months April and May 2011. The validated Roma Foundation questionnaire was used. This Foundation authorized its use by the Service of Gastroenterology Hospital Vargas de Caracas. 15 states were randomly selected, in each state one municipality, and in those places as churches, shopping centers, comunity meeting, bus stops, etc. The values obtained were transcribed into a database in Excel and processed EPIDAT 3.1. Of 1781 people encuested, 299 met the criteria for IBS according to Rome III. The national prevalence of IBS was 16.80%, with 81.6% women (244) and 18.4% men (55). The age group between 38 and 47 years was the most affected (26.43%) and the mix was the most predominant subtype. The prevalence of IBS in the Venezuelan adult population according to Rome III criteria is 16.80%

Alta incidencia de diarrea por clostridium difficile en pacientes nefrológicos / High frequency of clostridium difficile diarrhea among patients with renal diseases

Background: Clostridium difficile is the main agent causing antimicrobial associated nosocomial diarrhea. Chronic renal failure is a risk factor for this type of diarrhea. Aim: To study the incidence and complications of Clostridium difficile diarrhea in a university hospital and among patients with renal diseases. Patients and methods: Retrospective review of all cases of Clostridium difficile diarrhea that occurred in a university hospital, between June 2000 and May 2001. Results: In the Nephrology Unit, 48 episodes of Clostridium difficile diarrhea occurred in 35 patients (7 cases per 100 discharges/year). This figure is higher than the global incidence in the hospital (0.53 cases per 100 discharges/year, p <0.001). The mean age of the 33 patients with renal diseases was 63 years old and 17 of them were female. Their main diagnoses were chronic renal failure in hemodialysis in 48 percent , uremic syndrome in 36 percent and renal transplant in 6 percent. Seventy nine percent had a history of antimicrobial use (42 percent quinolones and 36 percent cephalosporins). In 3 patients, the only risk factor was chronic renal failure. Seventy five percent responded to metronidazole and in 27 percent, diarrhea recidivated, compared with a 6 percent recurrence rate in other units, p <0.02). Eight patients died during hospital stay. Conclusions: Among patients with renal diseases, Clostridium difficile is frequent and associated with a high recurrence rate and mortality. Chronic renal failure may be a risk factor for its development

Efecto de la midodrina en la hipotensión sintomática en hemodiálisis / Effects of midodrine on orthostatic hypotension during hemodialysis

Background: Hypotension occurs in 20 percent of hemodialysis procedures. Aim: To study the effects of midodrine on hypotension during hemodialysis. Patients and methods: Ten patients on chronic hemodialysis and with a history of hypotension during the procedure, were studied. They received midodrine 10 mg per os or placebo during 5 dialytic procedures each, in a double blind cross over design. Results: Blood pressure levels prior to dialysis were similar during the midodrine or placebo administration periods. During dialysis, systolic blood pressure fell 19.3ñ28 mmHg with midodrine and 23.4ñ28 mmHg with placebo. Diastolic blood pressure fell 7.3ñ11.5 mmHg with midodrine and 11.1ñ12 mmHg with placebo. The reduction in median arterial pressure was also less pronounced with midodrine. Conclusions: Midodrine lessens the fall in arterial pressure during hemodialysis, in patients with symptomatic hypotension

Enfermedad venooclusiva hepática asociada a terapia con azatioprina en un paciente trasplantado renal / Hepatic veno-occlusive disease associated to the use of azathioprine in a renal transplant recipient

We report a 30 years old male, recipient of a kidney allograft and treated with azathioprine, who 18 days after transplantation had a clinically asymptomatic elevation of total bilirrubin and alkaline phosphatases. Nineteen months later, he presented with mild ascites, with a total bilirrubin of 3.5 mg/dl, alkaline phosphatases of 308 U/L (normal <170 U/L) and a prothrombin time at 55 percent of control. A liver biopsy showed sinusoidal and perivenular fibrosis without inflammation, compatible with chronic venous obstruction. Hepatic veno-occlusive disease is an infrequent complication of azathioprine use