Subject(s)
Humans , Male , Aged , Aged, 80 and over , /complications , Renal Insufficiency, Chronic , Renal Replacement Therapy , DialysisABSTRACT
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Subject(s)
Humans , Male , Aged , Aged, 80 and over , Stroke/diagnostic imaging , Stroke/virology , Brain Ischemia/etiology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Betacoronavirus/isolation & purification , Coronavirus Infections/virology , Pneumonia, Viral/virology , Renal Insufficiency, Chronic/complications , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapyABSTRACT
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in this gene are major drivers of lung cancer development. EGFR tyrosine kinase inhibitors (TKIs) are standard firstline therapies for patients with advanced nonsmall cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wildtype EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wildtype NSCLC cells as single treatments or in combination with Fingolimod (FTY720), which has been approved for treating multiple sclerosis and has cytotoxic effects against several tumor cell lines. It was found that the combined treatment with TKIs lapatinib (Lap) or sorafenib (Sor) and FTY720 synergistically suppressed the viability of the NSCLC cell lines A549 and H596. Additionally, FTY720 inhibited lysosomal acidification and suppressed autophagy flux. Immunoblotting and reverse transcriptionquantitative polymerase chain reaction showed that FTY720 combined with Lap or Sor, enhanced endoplasmic reticulum (ER) stress loading and cell cycle arrest in A549 cells. The enhancement of ER stress loading and cell cycle arrest induced by combined treatment with Lap or Sor and FTY720, which was associated with the cytotoxicity induced by the combination of these drugs. These findings suggested that FTY720 improved TKI therapy in NSCLC patients with wildtype EGFR, by sensitizing NSCLC cells to TKIs.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cell Cycle/drug effects , Drug Resistance, Neoplasm/drug effects , Fingolimod Hydrochloride/pharmacology , Lung Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , A549 Cells , Autophagy-Related Proteins/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Repositioning , Drug Synergism , ErbB Receptors/genetics , Humans , Lapatinib/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Sorafenib/pharmacologyABSTRACT
Sabemos que el cambio climático afecta de forma considerable a la salud, si bien son muy pocos los estudios que recogen sus consecuencias a nivel renal. Se ha visto como las olas de calor aumentan la morbimortalidad cardiovascular y respiratoria, pero también el riesgo de fracaso renal agudo, así como el índice de ingresos de causa nefrológica, con la mortalidad que ello implica. Las situaciones de deshidratación repetidas en población expuesta de forma habitual a altas temperaturas parecen estar generando una nueva entidad dentro de la enfermedad renal crónica proteinúrica, cuyo mecanismo fisiopatológico se va dilucidando. Pero más allá de olas de calor y temperaturas extremas, se ha comprobado que existe una variación estacional del filtrado glomerular que pudiera facilitar el desarrollo de fracaso renal y alteraciones electrolíticas en periodos extremadamente cálidos. Entre las alteraciones del medio interno, parecen aumentar fundamentalmente las disnatremias, aunque es poca la evidencia bibliográfica al respecto. Los grupos de riesgo para presentar enfermedades asociadas al calor son ancianos, niños, enfermos crónicos, personas encamadas, discapacitados, sujetos que viven solos o con escaso contacto social y las poblaciones más desfavorecidas a nivel socioeconómico (AU)
It is well known that climate change greatly affects human health, even though there are few studies on renal outcomes. Heat waves have been found to increase cardiovascular and respiratory morbidity and mortality, as well as the risk of acute renal failure and hospitalisation due to renal diseases, with related mortality. Recurrent dehydration in people regularly exposed to high temperatures seems to be resulting in an unrecognised cause of proteinuric chronic kidney disease, the underlying pathophysiological mechanism of which is becoming better understood. However, beyond heat waves and extreme temperatures, there is a seasonal variation in glomerular filtration rate that may contribute to the onset of renal failure and electrolyte disorders during extremely hot periods. Although there are few references in the literature, serum sodium disorders seem to increase. The most vulnerable population to heat-related disease are the elderly, children, chronic patients, bedridden people, disabled people, people living alone or with little social contact, and socioeconomically disadvantaged people (AU)
Subject(s)
Humans , Kidney Diseases/epidemiology , Hot Temperature/adverse effects , Dehydration/complications , Acute Kidney Injury/epidemiology , Risk Factors , Heat Stress Disorders/complications , Body Temperature Regulation/physiology , Renal Insufficiency, Chronic/physiopathology , Water-Electrolyte Imbalance/physiopathologyABSTRACT
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Subject(s)
Humans , Renal Insufficiency, Chronic/complications , Hepatitis C, Chronic/drug therapy , Antiviral Agents/therapeutic use , Treatment OutcomeABSTRACT
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Subject(s)
Humans , Male , Aged , Glomerulonephritis/complications , Leprosy/complications , Mycobacterium leprae/pathogenicity , BiopsyABSTRACT
Background: Vitamin D has an important regulatory effect on the renin-angiotensin-aldosterone system, playing a central role in the regulation of proteinuria. We therefore studied the antiproteinuric effect of paricalcitol. Methods: 36 patients with an estimated GFR of 30-90mL/min/1.73m2 and proteinuria >400mg/d with a stable dose of ACE inhibitor or ARB for at least 3 months were recruited. Patients received oral paricalcitol 1µg/day for 12 months. Primary endpoint was decrease in proteinuria from baseline. Secondary endpoints were changes in creatinine, eGFR, serum levels of calcium, phosphorus, iPTH, 25(OH)vitD, C-Reactive Protein and blood presure. Results: Mean proteinuria was 2806mg/d and fell to 2199mg/d at month 6 (p<.0001) and 1931.5mg/d at month 12 (p<.0001). Patients with >3000mg/d baseline proteinuria (n=12) saw smaller relative reductions in proteinuria (5956.9±2492.6mg/d to 4220.4±2613mg/d at 12 months) than patients with <3000mg/d baseline proteinuria (1371±627.5 mg/d to 821.3±491.5mg/d at 12 months). There were no changes in BP, eGFR and CRP. We observed significant changes in serum levels of calcium, phosphorus, iPTH, 25(OH) vitamin D. Conclusion: Our study shows an important reduction in proteinuria with a low dose of oral paricalcitol in CKD, that is particularly robust with baseline proteinuria between 1-3g/d (AU)
Introducción: La vitamina D posee un efecto regulatorio del eje renina-angiotensina-aldosterona, jugando, por lo tanto, un papel importante en cuanto a proteinuria se refiere. Presentamos nuestra experiencia en el uso de paricalcitol como antiproteinúrico. Métodos: Incluimos 36 pacientes con un eGFR of 30-90 ml/min/1,73 m2 y proteinuria > 400 mg/d con dosis estables de inhibidores del SRAA durante 3 meses. Se le admistró durante 12 meses 1 µg/día de paricalcitol. Como objetivo primario estudiamos el descenso de proteinuria; como secundarios cambios en Cr, eFG, calcio, fósforo, iPTH, 25(OH)vitD, PCR y tension arterial. Resultados: La proteinuria media fue 2806 mg/d cayendo hasta 2199 mg/d en el mes 6 (p < 0,0001) y 1931,5 mg/d a los 12 meses (p < 0,0001). Aquellos con una proteinuria basal > 3000 mg/d (n=12) sufrieron una menor disminución (5956,9 ± 2492,6 mg/d a 4220,4 ± 2613 mg/d en mes 12) respecto a aquellos con una proteinuria < 3000 mg/d (1371 ± 627,5 mg/d a 821,3 ± 491,5 mg/d en mes 12). No se objetivaron cambios en tension arterial, eGFR y PCR. Los cambios en calcio, fósforo, iPTH y vitamina D 25(OH) fueron estadísticamente significativos. Conclusión: Nuestro estudio demuestra una reducción importante de proteinuria con dosis bajas de paricalcitol en pacientes con IRC, que es de particular importancia en aquellos con porteinuria basal entre 1-3 g/d (AU)
