A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression.

Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.

Timing of Meals and Sleep in the Mediterranean Population: The Effect of Taste, Genetics, Environmental Determinants, and Interactions on Obesity Phenotypes.

Circadian rhythms regulate the sleep-wake and feeding-fasting cycles. Sleep and feeding constitute a complex cycle that is determined by several factors. Despite the importance of sleep duration and mealtimes for many obesity phenotypes, most studies on dietary patterns have not investigated the contribution of these variables to the phenotypes analyzed. Likewise, they have not investigated the factors related to sleep or mealtimes. Thus, our aims were to investigate the link between taste perception and eating/sleep patterns and to analyze the effect of the interactions between sleep/meal patterns and genetic factors on obesity phenotypes. We conducted a cross-sectional analysis on 412 adults from the Mediterranean population. We measured taste perception (bitter, sweet, salty, sour, and umami) and assessed sleep duration and waketime. The midpoint of sleep and social jetlag was computed. From the self-reported timing of meals, we estimated the eating window, eating midpoint, and eating jetlag. Adherence to the Mediterranean diet was measured with a validated score. Selected polymorphisms in the TAS2R38, CLOCK, and FTO genes were determined, and their associations and interactions with relevant phenotypes were analyzed. We found various associations between temporal eating, sleep patterns, and taste perception. A higher bitter taste perception was associated with an earlier eating midpoint (p = 0.001), breakfast time (p = 0.043), dinner time (p = 0.009), waketime (p < 0.001), and midpoint of sleep (p = 0.009). Similar results were observed for the bitter taste polymorphism TAS2R38-rs713598, a genetic instrumental variable for bitter perception, increasing the causality of the associations. Moreover, significant gene-sleep interactions were detected between the midpoint of sleep and the TAS2R38-rs713598 (p = 0.032), FTO-rs9939609 (p = 0.037), and CLOCK-rs4580704 (p = 0.004) polymorphisms which played a role in determining obesity phenotypes. In conclusion, our study provided more information on the sleep and mealtime patterns of the general Spanish Mediterranean population than on their main relationships. Moreover, we were able to show significant associations between taste perception, specifically bitter taste; sleep time; and mealtimes as well as an interaction between sleep time and several genetic variants linked to obesity phenotypes. However, additional research is needed to better characterize the causality and mechanisms behind these associations.

The GenoDiabMar Registry: A Collaborative Research Platform of Type 2 Diabetes Patients.

The GenoDiabMar registry is a prospective study that aims to provide data on demographic, biochemical, and clinical changes in type 2 diabetic (T2D) patients attending real medical outpatient consultations. This registry is also used to find new biomarkers related to the micro- and macrovascular complications of T2D, with a particular focus on diabetic nephropathy. With this purpose, longitudinal serum and urine samples, DNA banking, and data on 227 metabolomics profiles, 77 immunoglobulin G glycomics traits, and other emerging biomarkers were recorded in this cohort. In this study, we show a detailed longitudinal description of the clinical and analytical parameters of this registry, with a special focus on the progress of renal function and cardiovascular events. The main objective is to analyze whether there are differential risk factors for renal function deterioration between sexes, as well as to analyze cardiovascular events and mortality in this population. In total, 650 patients with a median age of 69 (14) with different grades of chronic kidney disease­G1−G2 (eGFR > 90−60 mL/min/1.73 m2) 50.3%, G3 (eGFR; 59−30 mL/min/1.73 m2) 31.4%, G4 (eGFR; 29−15 mL/min/1.73 m2) 10.8%, and G5 (eGFR < 15 mL/min/1.73 m2) 7.5%­were followed up for 4.7 (0.65) years. Regardless of albuminuria, women lost 0.93 (0.40−1.46) fewer glomerular filtration units per year than men. A total of 17% of the participants experienced rapid deterioration of renal function, 75.2% of whom were men, with differential risk factors between sexes­severe macroalbuminuria > 300 mg/g for men OR [IQ] 2.40 [1.29:4.44] and concomitant peripheral vascular disease 3.32 [1.10:9.57] for women. Overall mortality of 23% was detected (38% of which was due to cardiovascular etiology). We showed that kidney function declined faster in men, with different risk factors compared to women. Patients with T2D and kidney involvement have very high mortality and an important cardiovascular burden. This cohort is proposed as a great tool for scientific collaboration for studies, whether they are focused on T2D, or whether they are interested in comparing differential markers between diabetic and non-diabetic populations.

Podocytopathy in patients with monoclonal gammopathy: three patients and literature review.

BACKGROUND: Renal manifestations of monoclonal gammopathies are of increasing interest among nephrologists. Typical manifestations include light chain cast nephropathy, amyloidosis or renal damage mediated by monoclonal immunoglobulin deposition. Podocytopathies in the setting of an underlying monoclonal gammopathy constitute a rare manifestation of these diseases and, although being described in the literature, remain a challenge since most data derive from case reports. METHODS: A retrospective review of the clinical data of Hospital del Mar and Hospital Vall d'Hebron was performed to identify patients with minimal change disease (MCD) or focal and segmental glomerulosclerosis (FSGS) in the setting of neoplasms that produce monoclonal (M) protein. Additionally, a literature review on this topic was performed. This study aims to describe the clinical characteristics and outcomes of these patients. RESULTS: Three patients were identified to have podocytopathy and monoclonal gammopathy between the years 2013 and 2020. All three were males and  >65 years of age. Two patients were diagnosed with MCD and one patient was diagnosed with FSGS. All patients underwent a kidney biopsy and light and electron microscopic studies were performed. The underlying causes of monoclonal gammopathy were multiple myeloma in two cases and Waldeström macroglobulinemia in one case. Two patients developed nephrotic syndrome during the follow-up. All patients were under active hematological treatment. One patient presented a complete remission of proteinuria whereas the other two presented a partial remission. CONCLUSIONS: Podocytopathies may infrequently be found in patients with monoclonal gammopathies. Patients with overt glomerular proteinuria and hematological disorders with M protein should undergo a kidney biopsy for prompt diagnosis and to specify a prognosis. In addition, further study on this matter must be done to understand the pathophysiology and treat these patients appropriately.

Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes.

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.

IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates ß1-integrin/FAK signalling in human podocytes.

AIMS/HYPOTHESIS: Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. METHODS: IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. RESULTS: Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)-forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via ß1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. CONCLUSIONS/INTERPRETATION: This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD.

Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes.

Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.

Bovine Interferon-Tau Activates Type I interferon-Associated Janus-signal Transducer in HPV16-positive Tumor Cell.

The mechanisms of signal transduction by interferon-tau (IFN-τ) are widely known during the gestation of ruminants. In trophoblast cells, IFN-τ involves the activation of the JAK-STAT pathway, and it can have effects on other cell types, such as tumor cells. Here we report that the HPV16-positive BMK-16/myc cell treated with ovine IFN-τ, results in the activation of the canonical JAK-STAT and non-canonical JAK-STAT pathway. The MAPK signaling pathway was activated, we detected the proteins MEK1, MEK2, Raf1, STAT3, STA4, STAT5 and STAT6. Moreover, IFN-τ induced the expression of MHC Class I, MX and IP10 in the tumor cells and this response may be associated with the viral replication and with the anti-proliferative and the immunoregulatory effects of IFN-τ.

Síndrome de burnout y la satisfacción laboral en profesionales de la salud / Burnout syndrome and job satisfaction in health professionals

Objetivo: Determinar las relaciones funcionales entre el burnout y la satisfacción laboral de los profesionales de la salud de dos hospitales del Perú. Materiales y métodos: Estudio cuantitativo, observacional, correlacional de corte transversal. De una población de 620 profesionales de la salud se encuestaron a 177 profesionales (médicos, odontólogos, químicos farmacéuticos, psicólogos, enfermeros, obstetras, tecnólogos médicos, nutricionistas y trabajadores sociales). Los instrumentos de medición utilizados fueron el inventario de burnout de Maslach (MBI) y la escala de satisfacción laboral (SL-SPC), cuyas propiedades psicométricas fueron adecuadas. Resultados: La tasa de prevalencia (TP) para el burnout alto fue 33,3 %. Mediante el análisis de ecuaciones estructurales, se encontró que existe relación significativa (AGFI = 0,946) y negativa (coeficiente estructural = -0,62) entre el burnout y la satisfacción laboral en los profesionales de la salud. La dimensión predominante del burnout fue la despersonalización (37 %=0,72/ (0,56+0,72+0,65); y el factor predominante de la satisfacción laboral fueron los beneficios económicos (35 %=0,99/ (0,67+0,99+0,48+0,66). Conclusiones: Existe relación funcional significativa y negativa entre el síndrome de burnout y la satisfacción laboral; el burnout es predictor de la satisfacción laboral. No se han encontrado diferencias significativas al comparar la tasa de prevalencia del burnout alto, según las variables sociodemográficas y laborales.

Objective: To estimate the functional relationships between burnout and job satisfaction in health professionals of two hospitals in Peru.Materials and methods: A quantitative, observational, correlational and cross-sectional research was carried out. Out of a study population of 620 health professionals, 177 (physicians, odontologists, pharmacists, psychologists, nurses, obstetricians, medical technologists, nutritionists and social workers) were interviewed. The Maslach Burnout Inventory (MBI) and the Job Satisfaction Scale (SL-SPC) were used as measuring instruments, showing adequate psychometric properties.Results: The high-burnout prevalence rate (TP) was 33.3 %. Using a structural equation analysis, a significant (AGFI = 0.946) and negative (structural coefficient = -0.62) relationship was found between burnout and job satisfaction in health professionals. The predominant dimension of burnout was depersonalization (37 % = 0.72 / (0.56 + 0.72 + 0.65)) and the predominant factor of job satisfaction was profits (35 % = 0.99 / (0.67 + 0.99 + 0.48 + 0.66)). Conclusions: There is a significant and negative functional relationship between burnout syndrome and job satisfaction. Burnout is a predictor of job satisfaction. No significant differences were found when comparing the high-burnout prevalence rate regarding the sociodemographic and work-related variables.

Quantitative proteomics reveals proteins involved in the progression from non-cancerous lesions to gastric cancer.

Gastric cancer is one of the most aggressive malignancies affecting humankind. With almost a million cases globally, it sits in fifth position in terms of incidence, and third in terms of mortality. The progression of this disease is slow, with prolonged and sequential precancerous stages including chronic gastritis, intestinal metaplasia, dysplasia, and finally gastric cancer. Here we used the iTRAQ approach combined with high-resolution mass spectrometry analysis to describe the spectrum of the gastric cancer cascade. Biopsies from three stages: chronic gastritis, intestinal metaplasia, and gastric adenocarcinoma, were selected for analysis by quantitative proteomics. We identified and reported quantitative data for 3914 different proteins quantified with high confidence, uncovering pathways and processes dysregulated between the different stages. Intestinal metaplasia is characterized by the down-regulation of ribosomal proteins, with overexpression of cell survival proteins such as GSTP1 and EPCAM. The transformation to gastric cancer involves overexpression of the DNA replication and the spliceosome pathways. The impairment of mitochondrial pathways was correlated with down-regulation of SIRT3 and SIRT5, and overexpression of enzymes supporting the glycolytic phenotype, such as HK3 and PCK2. Several proteins found dysregulated during the progression of gastric cancer have potential to be used as specific biomarkers and/or therapeutic targets.

A Multi-Locus Genetic Risk Score for Primary Open-Angle Glaucoma (POAG) Variants Is Associated with POAG Risk in a Mediterranean Population: Inverse Correlations with Plasma Vitamin C and E Concentrations.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. The genetics of POAG are complex, and population-specific effects have been reported. Although many polymorphisms associated with POAG risk have been reported, few studies have analyzed their additive effects. We investigated, in a southern European Mediterranean population, the association between relevant POAG polymorphisms, identified by initial genome-wide association studies (GWASs) and POAG risk, both separately and as an aggregated multi-locus genetic risk score (GRS). Also, bearing in mind that oxidative stress is a factor increasingly recognized in the pathogenesis of POAG, we analyzed the potential association of the GRS with plasma concentrations of antioxidant vitamins (C and E). We carried out a case-control study including 391 POAG cases and 383 healthy controls, and analyzed four genetic polymorphisms (rs4656461-TMCO1, rs4236601-CAV1/CAV2, rs2157719-CDKN2B-AS1 and rs3088440-CDKN2A). An unweighted GRS including the four non-linked polymorphisms was constructed. A strong association between the GRS and POAG risk was found. When three categories of the GRS were considered, subjects in the top category of the GRS were 2.92 (95% confidence interval (CI): 1.79-4.77) times more likely to have POAG compared with participants in the bottom category (p < 0.001). Moreover, the GRS was inversely correlated with plasma vitamin C (p = 0.002) and vitamin E (p = 0.001) concentrations, even after additional adjustment for POAG status. In conclusion, we have found a strong association between the GRS and POAG risk in this Mediterranean population. While the additional correlation found between GRS and low levels of vitamins C and E does not indicated a causal relationship, it does suggest the need for new and deeper research into the effects of oxidative stress as a potential mechanism for those associations.

Interferon-Tau has Antiproliferative effects, Represses the Expression of E6 and E7 Oncogenes, Induces Apoptosis in Cell Lines Transformed with HPV16 and Inhibits Tumor Growth In Vivo.

Interferon tau (IFN-τ) is a promising alternative antiviral and immunotherapeutic agent in a wide variety of diseases including infectious, neurodegenerative, autoimmune and cancer due to its low toxicity in comparison with other type I interferon´s. The objective of our study was established the effect of the bovine IFN-τ on human (SiHa) and murine (BMK-16/myc) cells transformed with HPV 16 and evaluates the antitumor effect in a murine tumor model HPV 16 positive. We determine that bovine IFN-τ has antiproliferative effects, pro-apoptotic activity and induces repression of viral E6 and E7 oncogenes (time- and dose-dependent) on human and murine cells transformed with HPV 16 similar to the effects of IFN-ß. However, IFN-τ induces greater antiproliferative effect, apoptosis and repression of both oncogenes in BMK-16/myc cells compared to SiHa cells. The differences were explained by the presence and abundance of the type I interferon receptor (IFNAR) in each cell line. On the other hand, we treated groups of tumor-bearing mice (HPV16 positive) with IFN-τ and showed the inhibition tumor growth effect in vivo. Our finding indicates that bovine IFN-τ may be a good candidate for immunotherapy against cervical cancer.

Conocimiento y creencias de mujeres del estado de Morelos sobre el virus del papiloma humano / Knowledge and beliefs of women from the state of Morelos about the human papilloma virus

Introducción: una enfermedad de transmisión sexual que afecta a un alto porcentaje de mujeres jóvenes de todo el mundo es la infección producida por virus papiloma humano. La falta de información asociada a diversos factores culturales, favorece el desarrollo de creencias que dificultan la prevención y diagnóstico oportunos. Objetivo: identificar el nivel de conocimiento y las creencias que tienen las mujeres del Estado de Morelos, México, sobre la transmisión, detección y tratamiento de la infección por virus del papiloma humano de acuerdo con la edad y el grado de escolaridad. Métodos: estudio descriptivo transversal a partir de un cuestionario aplicado a 690 mujeres en el estado de Morelos. Resultados: el nivel de conocimientos entre la mayoría de la población femenina fue de nivel medio, se incrementa en mujeres jóvenes y con mayor escolaridad. La creencia de que la detección de infección implica mayor gasto económico se presenta sin distinción de edad o nivel escolar. Conclusiones: los aspectos más conocidos sobre la infección por virus papiloma humano, es que es una infección de transmisión sexual, asociada a la aparición de verrugas en genitales y causante de cáncer cérvico uterino. Los menos conocidos son: que la infección es asintomática y que no existe tratamiento para eliminarla(AU)

Introduction: A sexually transmitted disease affecting a high percentage of young women worldwide in the infection produced by the human papilloma virus (HPV). The lack of information associated with different cultural factor favors the development of beliefs that limit timely prevention and diagnosis. Objective: Identify the level of knowledge and beliefs of women from the state of Morelos, Mexico, about the transmission, detection and treatment of HPV infection in accordance with their age and school level. Methods: Cross-sectional, descriptive study with a survey conducted on 690 women on the state of Morelos. Results: The level of knowledge among most of the female population was average, increased in young women and those with higher school level. The belief that infection detection implies higher economic spends is present regardless age and school level. Conclusions: The most known aspects about HPV are that it is a sexually transmitted infection, associated to the onset of genital warts and causing cervical cancer. The least known are that the infection is asymptomatic and that there is no treatment to eliminate it(AU)

Conocimiento y creencias de mujeres del estado de Morelos sobre el virus del papiloma humano / Knowledge and beliefs of women from the state of Morelos about the human papilloma virus

Introducción: una enfermedad de transmisión sexual que afecta a un alto porcentaje de mujeres jóvenes de todo el mundo es la infección producida por virus papiloma humano. La falta de información asociada a diversos factores culturales, favorece el desarrollo de creencias que dificultan la prevención y diagnóstico oportunos. Objetivo: identificar el nivel de conocimiento y las creencias que tienen las mujeres del Estado de Morelos, México, sobre la transmisión, detección y tratamiento de la infección por virus del papiloma humano de acuerdo con la edad y el grado de escolaridad. Métodos: estudio descriptivo transversal a partir de un cuestionario aplicado a 690 mujeres en el estado de Morelos. Resultados: el nivel de conocimientos entre la mayoría de la población femenina fue de nivel medio, se incrementa en mujeres jóvenes y con mayor escolaridad. La creencia de que la detección de infección implica mayor gasto económico se presenta sin distinción de edad o nivel escolar. Conclusiones: los aspectos más conocidos sobre la infección por virus papiloma humano, es que es una infección de transmisión sexual, asociada a la aparición de verrugas en genitales y causante de cáncer cérvico uterino. Los menos conocidos son: que la infección es asintomática y que no existe tratamiento para eliminarla(AU)

Introduction: A sexually transmitted disease affecting a high percentage of young women worldwide in the infection produced by the human papilloma virus (HPV). The lack of information associated with different cultural factor favors the development of beliefs that limit timely prevention and diagnosis. Objective: Identify the level of knowledge and beliefs of women from the state of Morelos, Mexico, about the transmission, detection and treatment of HPV infection in accordance with their age and school level. Methods: Cross-sectional, descriptive study with a survey conducted on 690 women on the state of Morelos. Results: The level of knowledge among most of the female population was average, increased in young women and those with higher school level. The belief that infection detection implies higher economic spends is present regardless age and school level. Conclusions: The most known aspects about HPV are that it is a sexually transmitted infection, associated to the onset of genital warts and causing cervical cancer. The least known are that the infection is asymptomatic and that there is no treatment to eliminate it(AU)

In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer.

Human papillomavirus (HPV) is a DNA virus that infects epithelial cells and has been implicated in the development of cervical cancer. Few therapeutic strategies have been designed for the treatment of cervical intraepithelial neoplasia, a precursor of cervical cancer. In these early stages, the HPV E2 protein is the most important viral factor involved in viral gene expression and plays crucial roles during the vegetative viral cycle in epithelial cells. Papillomavirus E2 binds specifically to palindromic ACCN6GGT sequences, referred to as the E2 binding sites (E2BS), which are concentrated within the viral long control region, and which are responsible for regulation of the HPV protein's expression. Here, we consider E2BS as a candidate sequence to induce the expression of antiviral therapeutic genes selectively in HPV-infected cells expressing the E2 protein. This study focuses on the use of an HPV-specific promoter comprised of four E2BS to drive the expression of IL-12, leading to an antitumor effect in an HPV-positive murine tumor model. The therapeutic strategy was implemented via viral gene therapy using adenoviral vectors with recombinant E2 and IL-12 genes and E2BS-IL-12. We demonstrate that the HPV-specific promoter E2BS is functional in vitro and in vivo through transactivation of HPV E2 transcription factor.

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes.

Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2(-/-)). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2(-/-) podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2(-/-) podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

Beneficios del descanso peritoneal / Benefits of peritoneal rest

Introducción: Valorar si el descanso peritoneal, de al menos un día semanal, ha supuesto mejoras en la rehabilitación de los pacientes y el impacto clínico que puede suponer. Nos planteamos además cuantificar el beneficio económico. Material y Método: Se realizó un estudio longitudinal, retrospectivo, descriptivo. De los pacientes atendidos en nuestra unidad desde el 1 de enero de 2014 al 31 de diciembre de 2014, se estudiaron los pacientes que cumplieran todo el año de seguimiento y que no procedieran de otras técnicas de depuración como la hemodiálisis o trasplante renal. La muestra de estudio estuvo compuesta por 40 pacientes, de los que 21 tuvieron prescrito al menos 1 día semanal de descanso peritoneal y 19 pacientes sin descanso. Se recogieron las siguientes variables al inicio del periodo de estudio y a los 12 meses: Variables demográficas, variables relacionadas con el estado de volumen, datos clínicos relacionados con la técnica, se pasó una encuesta de satisfacción a todos los pacientes estudiados, y se recogieron los importes del coste mensual de cada tipo de tratamiento. Resultados: Las diferencias iniciales entre los grupos, eran esperables ya que son los valores en los cuales se ha basado la prescripción del día de descanso. La exposición a la glucosa, al comienzo y al final fue menor en el grupo con descanso. Al año, no se encontró diferencias en los parámetros estudiados. Una encuesta de satisfacción nos reveló a que dedican los pacientes el día de descanso y los que no lo tienen a que lo dedicarían. Conclusiones: El descanso peritoneal no ha supuesto una peor evolución de los parámetros clínicos estudiados al año de seguimiento, cumpliendo las recomendaciones de adecuación de diálisis de las guías clínicas. La exposición a la glucosa, aun sin llegar a ser significativa por la duración del estudio, ha sido menor en el grupo con descanso. El día de descanso ha facilitado a los pacientes mejorar su rehabilitación social principalmente. Los días de descanso han supuesto un ahorro de al menos 13,33% en la factura mensual (AU)

Introduction: To assess whether the peritoneal rest at least one day a week has led to improvements in the rehabilitation of patients, and the clinical impact that can be achieved. We also propose to quantify the economic benefit. Material and methods: A longitudinal, retrospective, descriptive study was conducted. Of those patients seen in our unit from 1 January 2014 to 31 December 2014, patients who fulfilled all the monitoring year and that at the same time they were not subjected to other purification techniques such as dialysis or transplantation kidney were studied. The study sample was composed of 40 patients, of whom 21 had prescribed at least 1 weekly day of peritoneal rest, and 19 patients without rest. The following variables at baseline and 12 months of the study period were recorded: Demographic variables, variables related to volume status, clinical data related to the technique and data related to a satisfaction survey, as well as the amounts of the monthly cost of each type of treatment. Resultados: The initial differences between the groups were expected since they are the values on which is based the prescription of the rest day. Exposure to glucose at the beginning and the end was lower in the group with rest. At one year, no differences in the studied parameters were found. A satisfaction survey revealed to us the activity that patients spend the rest day, as well as the activity that would perform those who not rest. Conclusiones: The peritoneal rest has not meant a worse outcome of the clinical parameters studied at one year, fulfilling the recommendations of dialysis adequacy of the guidelines. Although not statistically significant for the duration of the study, exposure to glucose was lower in the group with rest. The rest day has mainly provided to patients to improve their social rehabilitation. Rest days have generated savings on the monthly bill of 13.33% (AU)

Renin-angiotensin system within the diabetic podocyte.

Diabetic kidney disease is the leading cause of end-stage renal disease. Podocytes are differentiated cells necessary for the development and maintenance of the glomerular basement membrane and the capillary tufts, as well as the function of the glomerular filtration barrier. The epithelial glomerular cells express a local renin-angiotensin system (RAS) that varies in different pathological situations such as hyperglycemia or mechanical stress. RAS components have been shown to be altered in diabetic podocytopathy, and their modulation may modify diabetic nephropathy progression. Podocytes are a direct target for angiotensin II-mediated injury by altered expression and distribution of podocyte proteins. Furthermore, angiotensin II promotes podocyte injury indirectly by inducing cellular hypertrophy, increased apoptosis, and changes in the anionic charge of the glomerular basement membrane, among other effects. RAS blockade has been shown to decrease the level of proteinuria and delay the progression of chronic kidney disease. This review summarizes the local intraglomerular RAS and its imbalance in diabetic podocytopathy. A better understanding of the intrapodocyte RAS might provide a new approach for diabetic kidney disease treatment.

Genetic polymorphism related to exfoliative glaucoma is also associated with primary open-angle glaucoma risk.

BACKGROUND: To investigate the possible association of the rs2165241 polymorphism (C > T) in LOXL1 gene with the risk of primary open-angle glaucoma in a Mediterranean population. METHODS: The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique, using a 7900HT Sequence Detection System (Applied Biosystems). RESULTS: In a recessive genetic model, the T allele of the rs2165241 polymorphism was significantly associated with the risk of primary open-angle glaucoma (TT vs. CC: odds ratios = 2.19, 95% confidence interval = [1.33-3.62]). After multivariate logistic regression model adjusted by age and weight, the magnitude of the association decreased but remained statistically significant (TT vs. CC: odds ratios = 2.07, 95% confidence interval = [1.20-3.57]). CONCLUSION: This polymorphism seems to be associated with high risk for primary open-angle glaucoma in a Mediterranean population.

Inhibición de mTOR, proteínas Akt y enfermedad renal crónica / mTOR inhibition, Akt proteins and chronic kidney disease

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