RESUMEN
Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16(INK4A) expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16(INK4A) downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial-mesenchymal transition state. By contrast, increase in p16(INK4A) level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16(INK4A)-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16(INK4A)-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16(INK4A)-proficient fibroblasts. These results provide the first indication that p16(INK4A) downregulation in breast stromal fibroblasts is an important step toward their activation.
Asunto(s)
Neoplasias de la Mama/patología , Mama/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Fibroblastos/patología , Células del Estroma/patología , Actinas/genética , Actinas/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Ribonucleoproteína Nuclear Heterogénea D0 , Ribonucleoproteína Heterogénea-Nuclear Grupo D/genética , Humanos , Metaloproteinasa 2 de la Matriz/genética , Ratones , ARN Mensajero/metabolismo , ARN Interferente Pequeño , Células del Estroma/citología , Células del Estroma/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Out of 208 primary health care centres (PHCCs) in the Asir region, southwestern Saudi Arabia, a stratified random sample of 23 PHCCs was randomly chosen. Data regarding all the medical consultations (66,438) provided by all PHCCs physicians (49) and their prescriptions were collected to study prescribing patterns. The data were collected from the health information system of the PHCCs without the physicians' knowledge. The study showed that more than two-thirds of medical consultations (71.5%, 47,494) ended by prescribing medications. The average number of drug items prescribed for the individual patient was 1.44. The leading missing items in the studied prescriptions were, for how long should medication be taken (32.9%), the patient's name (15.8%) and the family health record number (6.5%). Prescribing drugs by generic name is very minimal among physicians (2.9%). The groups of drugs commonly prescribed were analgesics-antipyretics (61.9%), antibiotics (56.2%), cough medications (26.6%) and vitamins (22.7%). The observed defects identify fields to be addressed in continuing medical education programmes aimed at encouraging more rational prescribing among PHC physicians.
RESUMEN
OBJECTIVES: To investigate the cesarean section (CS) rate in the Riyadh area, its trend and relationship to perinatal mortality (PNM). METHODS: Based on delivery data obtained from the Ministry of Health hospitals, Saudi Arabia, for a total of 12 years, yearly rates of CS, PNM and the ratios of obstetricians and beds per 10,000 population were computed for the Riyadh area and compared with the overall rates for Saudi Arabia. Correlation coefficients were used to investigate the relationship between the CS rate and each of the stated variables. RESULTS: Riyadh had significantly lower rates of CS and PNM than Saudi Arabia as a whole. The CS rate in Riyadh showed a positive trend (increasing from 4.4 to 6.7%) while the PNM rate revealed a significant decreasing trend (decreasing from 21.6/1000 to 16/1000 live births). A negative association existed between the Riyadh rates of PNM and CS (r = -0.2375) and PNM and the availability of obstetricians (r = -0.8693). CONCLUSIONS: From our data it was not possible to establish a cause and effect relationship between the CS and PNM rates.
Asunto(s)
Cesárea/estadística & datos numéricos , Mortalidad Infantil , Cesárea/tendencias , Femenino , Humanos , Mortalidad Infantil/tendencias , Recién Nacido , Embarazo , Arabia Saudita/epidemiologíaRESUMEN
The present study was designed to investigate the reasons for which patients are referred by G.Ps to G.M. specialists, and to assess the extent to which referred cases need specialist care. The study sample included specialists of general medicine working at 4 of the H.I.O. polyclinics and all G.Ps who referred cases that were considered as inappropriate referrals by the study specialists, as well as 20% of Patients referred to G.M. specialists by G.Ps. were systematically randomly selected during a period of 10 consecutive days. The results indicated that the rate of inappropriate referral to G.M. specialists was high, the rate of discrepancy between G.P. and specialist diagnoses was generally high, there was a high discrepancy between G.Ps and specialists regarding the reason for inappropriate referral, and there was poor communication from the lower (G.P.) to the higher (specialists) levels in the referral process. Reasons for referral to specialists were not recorded by G.Ps in 100% of cases. To overcome these problems H.I.O. should place special emphasis on the professional training and continuing education of G.Ps, with special attention to the few common conditions that were responsible for the greater proportion of referral problems. At the same time, H.I.O. should strengthen the technical and administrative control over G.P. referral behavior.
Asunto(s)
Competencia Clínica , Médicos de Familia/normas , Derivación y Consulta/normas , Diagnóstico Diferencial , Egipto , HumanosRESUMEN
This study was conducted at 4 of the H.I.O. polyclinics in Alex. with the objective of examining the change in visit rate per 1000 beneficiaries for general medicine specialty at H.I.O. clinics during a 4-year period (1985-1988) and to detect any trends that may have a bearing on the H.I.O. standards for supply of specialists. Data were collected from H.I.O. statistics department, H.I.O. regulations, and also through researcher's observation and specialists' interview. The collected data was used to describe the workload in terms of annual visit rate, actual number of working hours, the specialists' average production hours per day, the specialists' average idle time per day, the estimated number of required specialist working hours per day, and the specialists' recommended working hours per day. The results revealed a rising trend in the rate of use of general medicine specialist services and a definite shortage of supply of general medicine specialists was found in all clinics compared to H.I.O. standards. On the other hand, recommended supply based on specialist opinion was less than the H.I.O. standards but more than the current supply. Accordingly H.I.O. should re-estimate the specialist population standard and should seek the commitment of specialists to the revised standards.