RESUMEN
BACKGROUND: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). METHODS: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit(-/-) embryos (AMPKα1/2(-/-)-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). RESULTS: Metformin (2.5 µM-5 mM) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)-AMPK-p53/p21(cip1) and inhibited the Akt-mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2(-/-)-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM-AMPK-p53/p21(cip1) and inhibition of Akt-mTOR-4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. CONCLUSION: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM-AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC.
Asunto(s)
Adenilato Quinasa/fisiología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Proteínas de Ciclo Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/fisiología , Neoplasias Pulmonares/radioterapia , Metformina/uso terapéutico , Proteínas Serina-Treonina Quinasas/fisiología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Proteínas Supresoras de Tumor/fisiología , Adenilato Quinasa/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Embrión de Mamíferos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metformina/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Proteínas Supresoras de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The microsurgical anatomy of the oculomotor nerve through its intraorbital course and branching was studied in 30 specimens obtained from 15 cadaver heads fixed in formalin. The superior and inferior divisions of the oculomotor nerve were shown and neural and vascular relationships of each division were examined, then some measurements were performed. In this part of the oculomotor nerve, some critical key points to the various orbital approaches were determined and microanatomic relationships of the orbital contents were revised.
Asunto(s)
Microcirugia , Nervio Oculomotor/anatomía & histología , Órbita/inervación , Humanos , Músculos Oculomotores/inervación , Nervio Oculomotor/cirugía , Órbita/cirugía , Valores de ReferenciaRESUMEN
This paper describes perceptions of familiarity with symptoms and beliefs about illnesses based on interviews with 50 Saudi women. The sample was young, with 82% under the age of 40, and not well educated by Western standards, with one-third being illiterate and 80% having no more than a primary school education. More than half lived in households of six or more. Although there was greater awareness of germs as causative factors in illness than previous studies in Saudi Arabia had demonstrated, beliefs in multiple causes, including religious beliefs about disease causation, persisted. There was an apparent lack of understanding of specific causes of various illnesses or of the rationale for preventive measures. This lack of understanding may be related to the low education levels and/or deeply ingrained cultural beliefs.
PIP: This study describes the types of knowledge and beliefs held by 50 Saudi women during 1984-85 in Riyadh, Saudi Arabia. Interviews were conducted in Arabic at 2 urban community health clinics and 1 urban pediatric clinic by bilingual female Egyptian and Saudi nursing faculty members. The study women believed in the tenets of Wahhabism, a conservative version of Islam prevalent in Saudi Arabia. All wore complete vessel in public and traveled in the company of a female or family member. A pilot study with 11 Saudi women was used to develop the questionnaire, which focused on 8 illnesses and their symptoms. Health beliefs referred to beliefs about the severity, prevention, and cure of illness. Health status and illness-related knowledge and behavior were also queried. Sociodemographic data were also requested for respondent, spouse, and children, age, marital status, educational level, household size, and family type. The sample was 82% women 40 years and 80% married (18% divorced). 36% lived in shared households (16%) or extended families, and 48% were members of nuclear families. 36% were illiterate and 44% had only a primary education. The influence of the evil eye belief may be reflected in the belief that 70% reported their family's health about the same as others. 54% of the women reported family members having a respiratory illness within the last 4 weeks, but only 24% recognized the "air" as a means of transmission. Common childhood illnesses were recognized. There was less familiarity with tuberculosis or chest disease; around 25% would rely on a doctor for a diagnosis. Vaccinations were considered necessary, and children's health was valued. God was believed to be the primary cause of illness by 10% and to be a contributory cause by 20-30%. More than 50% believed that extreme shifts in temperature were the cause of diarrhea, chest disease, and epistaxis. Measles and diarrhea were viewed as serious diseases. Modern medicine's impact may be reflected in the few who recognized germs as a cause of disease and mentioned, several causes for diseases. In general, little understanding was shown for causes of various illnesses or the rationale for prevention in vaccination. Among these women prevention may be a concept which conflicts with God's will.