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Adherence to hand hygiene procedures is crucial for all populations, and the World Health Organization (WHO) has implemented specific guidelines for infection control. Frequent and correct hand hygiene can prevent infections, but non-compliance with hand hygiene is pervasive. Nursing students address this issue from the beginning of their training. In nursing training, self-efficacy is crucial in enhancing students' competence, motivation, and clinical performance. We performed a cross-sectional multicenter study in five European countries, with a cross-sectional design with an online application of an instrument measuring hand hygiene knowledge based on WHO guidelines and general self-efficacy and specific self-efficacy for infection control. A total of 638 first-year nursing students participated in this study. The mean percentage of correct answers was 67.9%, with a considerable difference depending on the items. The worst results were obtained for questions related to sources of infection and types of hand hygiene methods in different situations. Finnish students displayed significantly (p < 0.001) higher scores in HH knowledge, whereas Estonian students had significantly (p < 0.001) higher levels of self-efficacy. There were significant correlations between the hand hygiene knowledge score and the self-efficacy score (p < 0.001). A multivariate analysis by linear regression analysis showed significant associations between the hand hygiene knowledge survey score and the students' age (p < 0.001, OR = 0.18, 95% CI 0.04-0.10), as well as their country of origin (p = 0.01, OR = 0.09, 95% CI 0.03-0.34). HH knowledge is quite low among nursing students, and is correlated with self-efficacy, although the strongest predictors are age and country of origin. Different nursing curricula must favor HH knowledge, with varying degrees of emphasis depending on the country.
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Hospitals at home are increasingly offering outpatient parenteral antimicrobial therapy (OPAT) in an attempt to reduce costly inpatient care, but these settings favour broad-spectrum antibiotics that require less frequent dosing than penicillin. Benzyl penicillin could be delivered via continuous infusion pumps (eCIPs), but studies on their safety and efficacy in OPAT are scarce, and it remains unclear how much the availability of eCIPs increases penicillin use in real-life settings. We examined 462 electronic healthcare records of erysipelas patients treated between January 2018 and January 2022 in a large Finnish OPAT clinic. Average marginal effects from logistic models were estimated to assess how the introduction of eCIPs in December 2020 affected penicillin use and to compare clinical outcomes between patients with and without eCIPs. Introduction of eCIPs increased the predicted probability of penicillin treatment by 36.0 percentage points (95% confidence interval 25.5-46.5). During eCIP implementation, patients who received an eCIP had 73.1 (58.0-88.2) percentage points higher probability than patients without an eCIP to receive penicillin treatment. They also had about 20 percentage points higher probability to be cured at the time of discharge and 3 months after it. Patient and nurse satisfaction regarding eCIPs was very high. Benzyl penicillin eCIP treatment is effective and safe, and substantially increases the use of penicillin instead of broad-spectrum antibiotics. To reduce the risk of antimicrobial resistance, eCIPs could increasingly be promoted for use in OPAT clinics, and there should be adequate education and support in their implementation.
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BACKGROUND: Up to 35% of nurses' working time is spent on care documentation. We describe the evaluation of a system aimed at assisting nurses in documenting patient care and potentially reducing the documentation workload. Our goal is to enable nurses to write or dictate nursing notes in a narrative manner without having to manually structure their text under subject headings. In the current care classification standard used in the targeted hospital, there are more than 500 subject headings to choose from, making it challenging and time consuming for nurses to use. METHODS: The task of the presented system is to automatically group sentences into paragraphs and assign subject headings. For classification the system relies on a neural network-based text classification model. The nursing notes are initially classified on sentence level. Subsequently coherent paragraphs are constructed from related sentences. RESULTS: Based on a manual evaluation conducted by a group of three domain experts, we find that in about 69% of the paragraphs formed by the system the topics of the sentences are coherent and the assigned paragraph headings correctly describe the topics. We also show that the use of a paragraph merging step reduces the number of paragraphs produced by 23% without affecting the performance of the system. CONCLUSIONS: The study shows that the presented system produces a coherent and logical structure for freely written nursing narratives and has the potential to reduce the time and effort nurses are currently spending on documenting care in hospitals.
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Documentación , Enfermeras y Enfermeros , Automatización , Hospitales , Lenguaje , DescriptoresRESUMEN
BACKGROUND: Patient-derived xenografts (PDXs) are considered to better recapitulate the histopathological and molecular heterogeneity of human cancer than other preclinical models. Despite technological advances, PDX models from hormone naïve primary prostate cancer are scarce. We performed a detailed analysis of PDX methodology using a robust subcutaneous model and fresh tissues from patients with primary hormone naïve prostate cancer. METHODS: Clinical prostate tumor specimens (n=26, Gleason score 6-10) were collected from robotic-assisted laparoscopic radical prostatectomies at Turku University Hospital (Turku, Finland), cut into pieces, and implanted subcutaneously into 84 immunodeficient mice. Engraftments and the adjacent material from prostatic surgical specimens were compared using histology, immunohistochemistry and DNA sequencing. RESULTS: The probability of a successful engraftment correlated with the presence of carcinoma in the implanted tissue. Tumor take rate was 41%. Surprisingly, mouse hormone supplementation inhibited tumor take rate, whereas the degree of mouse immunodeficiency did not have an effect. Histologically, the engrafted tumors closely mimicked their parental tumors, and the Gleason grades and copy number variants of the engraftments were similar to those of their primary tumors. Expression levels of androgen receptor, prostate-specific antigen, and keratins were retained in engraftments, and a detailed genomic analysis revealed high fidelity of the engraftments with their corresponding primary tumors. However, in the second or third passage of tumors, the carcinoma areas were almost completely replaced by benign tissue with frequent degenerative or metaplastic changes. CONCLUSIONS: Subcutaneous primary prostate engraftments preserve the phenotypic and genotypic landscape. Thus, they serve a potential model for personalized medicine and preclinical research but their use may be limited to the first passage.
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An increase in cardiac output during pregnancy increases the risk of arrhythmias for the expectant mother. Supraventricular tachycardia (SVT) underlies the sensations of arrhythmia in a pregnant woman in as many as one sixth of the cases. Vagal nerve (n. vagus) stimulation and adenosine serve as first-line treatment, but electrical cardioversion is likely to be a safe alternative as well. We describe a case in which the SVT of a woman in the third trimester of pregnancy was unresponsive to vagal nerve stimulation and pharmacological treatments. Electrical cardioversion was successfully performed after having a cesarean section procedure.
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Cardioversión Eléctrica , Complicaciones Cardiovasculares del Embarazo/terapia , Taquicardia Supraventricular/terapia , Adulto , Cesárea , Femenino , Humanos , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico , Tercer Trimestre del Embarazo , Taquicardia Supraventricular/diagnósticoRESUMEN
LuCaP serially transplantable patient-derived xenografts (PDXs) are valuable preclinical models of locally advanced or metastatic prostate cancer. Using spheroid culture methodology, we recently established cell lines from several LuCaP PDXs. Here, we characterized in depth the features of xenografts derived from LuCaP 136 spheroid cultures and found faithful retention of the phenotype of the original PDX. In vitro culture enabled luciferase transfection into LuCaP 136 spheroids, facilitating in vivo imaging. We showed that LuCaP 136 spheroids formed intratibial, orthotopic, and subcutaneous tumors when re-introduced into mice. Intratibial tumors responded to castration and were highly osteosclerotic. LuCaP 136 is a realistic in vitro-in vivo preclinical model of a subtype of bone metastatic prostate cancer.
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Neoplasias Óseas/patología , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Esferoides Celulares/patología , Animales , Neoplasias Óseas/secundario , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (µCT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.
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Neoplasias Óseas/secundario , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias Óseas/patología , Supervivencia Celular , Modelos Animales de Enfermedad , Femenino , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Osteólisis , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite the pressing need to noninvasively monitor transplanted cells in vivo with fluorescence imaging, desirable fluorescent agents with rapid labeling capability, durable brightness, and ideal biocompatibility remain lacking. Here, phosphorylcholine-coated near-infrared (NIR) fluorescent semiconducting polymer nanoparticles (SPNs) are reported as a new class of rapid, efficient, and cytocompatible labeling nanoagents for in vivo cell tracking. The phosphorylcholine coating results in efficient and rapid endocytosis and allows the SPN to enter cells within 0.5 h in complete culture medium apparently independent of the cell type, while its NIR fluorescence leads to a tissue penetration depth of 0.5 cm. In comparison to quantum dots and Cy5.5, the SPN is tolerant to physiologically ubiquitous reactive oxygen species (ROS), resulting in durable fluorescence both in vitro and in vivo. These desirable physical and physiological properties of the SPN permit cell tracking of human renal cell carcinoma (RCC) cells in living mice at a lower limit of detection of 10 000 cells with no obvious alteration of cell phenotype after 12 d. SPNs thus can provide unique opportunities for optimizing cellular therapy and deciphering pathological processes as a cell tracking label.
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Rastreo Celular , Nanopartículas/química , Fosforilcolina/química , Polímeros/química , Animales , Carbocianinas/química , Línea Celular Tumoral , Células HeLa , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Nanopartículas/metabolismo , Puntos Cuánticos/química , Puntos Cuánticos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Semiconductores , Piel/patología , Espectroscopía Infrarroja Corta , Trasplante HeterólogoRESUMEN
mTOR is a rational target in renal cell carcinoma (RCC) because of its role in disease progression. However, the effects of temsirolimus, the only first-generation mTOR inhibitor approved by the FDA for first-line treatment of metastatic RCC, on tumor reduction and progression-free survival are minimal. Second-generation mTOR inhibitors have not been evaluated on RCC. We compared the effects of temsirolimus and MLN0128, a potent second-generation mTOR inhibitor, on RCC growth and metastasis using a realistic patient-derived tissue slice graft (TSG) model. TSGs were derived from three fresh primary RCC specimens by subrenal implantation of precision-cut tissue slices into immunodeficient mice that were randomized and treated with MLN0128, temsirolimus, or placebo. MLN0128 consistently suppressed primary RCC growth, monitored by magnetic resonance imaging (MRI), in three TSG cohorts for up to 2 months. Temsirolimus, in contrast, only transiently inhibited the growth of TSGs in one of two cohorts before resistance developed. In addition, MLN0128 reduced liver metastases, determined by human-specific quantitative polymerase chain reaction, in two TSG cohorts, whereas temsirolimus failed to have any significant impact. Moreover, MLN0128 decreased levels of key components of the two mTOR subpathways including TORC1 targets 4EBP1, p-S6K1, HIF1α and MTA1 and the TORC2 target c-Myc, consistent with dual inhibition. Our results demonstrated that MLN0128 is superior to temsirolimus in inhibiting primary RCC growth as well as metastases, lending strong support for further clinical development of dual mTOR inhibitors for RCC treatment.
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Benzoxazoles/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Animales , Carcinoma de Células Renales/patología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Immunoblotting , Neoplasias Renales/patología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/secundario , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Noqueados , Persona de Mediana Edad , Complejos Multiproteicos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Sirolimus/análogos & derivados , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
OBJECTIVE: Discovery of curative therapies for renal cell carcinoma (RCC) is hampered by lack of authentic preclinical models. Tumorgrafts, generated by direct implantation of patient-derived tissues into mice, have demonstrated superior ability to predict therapeutic response. We evaluated "tissue slice grafts" (TSGs) as an improved tumorgraft model of RCC. MATERIALS AND METHODS: Cores of fresh RCC were precision-cut at 300 µm and implanted under the renal capsule of RAG2(-/-)γC(-/-) mice. Engraftment rate, histology, biomarker expression, genetic fidelity, and metastatic potential were evaluated. Magnetic resonance imaging (MRI) was tested as a noninvasive method to measure tumor volume, and response to a targeted therapy was determined. RESULTS: All 13 cases of RCC engrafted and displayed characteristic histology and biomarkers. TSG volume quantified noninvasively by MRI highly correlated with graft weights, providing a unique tool for monitoring orthotopic growth. Moreover, in 2 cases, cancer cells from TSGs metastasized to clinically relevant sites, including bone. Microarray analysis and DNA sequencing demonstrated a high degree of correlation of global gene expression and von Hippel-Lindau (VHL) status between TSGs and parental tumors. Treatment of TSGs with sunitinib significantly decreased graft weight and mean vessel density compared with controls. CONCLUSION: The TSG model of RCC faithfully recapitulates tumor pathology, gene expression, genetic mutation, and drug response. The high engraftment rate and metastatic potential of this authentic model, in conjunction with the ability to generate large first-generation animal cohorts and to quantitate tumor volume at the orthotopic site by MRI, proffer significant advantages compared with other preclinical platforms.
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Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Trasplante Heterólogo/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Antineoplásicos/farmacología , Secuencia de Bases , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Femenino , Perfilación de la Expresión Génica , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/genética , Humanos , Indoles/farmacología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Datos de Secuencia Molecular , Metástasis de la Neoplasia , Pirroles/farmacología , Homología de Secuencia de Aminoácido , Sunitinib , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
BACKGROUND: Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. METHODS: Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG) and hypoxia ([18F]EF5), and intratumoral polarographic measurements of pO2. RESULTS: Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. CONCLUSION: FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.
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Factor 8 de Crecimiento de Fibroblastos/biosíntesis , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/metabolismo , Animales , Humanos , Hipoxia , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Oxígeno/química , Oxígeno/metabolismo , Pronóstico , Transfección , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. METHODS: We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice. RESULTS: VEGFR3-Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC-3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001). CONCLUSION: The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites.
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Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/patología , Factor C de Crecimiento Endotelial Vascular/genética , Animales , Línea Celular Tumoral , Linfangiogénesis , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/fisiopatología , Factor C de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Fibroblast growth factor 8 (FGF-8) is expressed at an increased level in a high proportion of prostate cancers and it is associated with a poor prognosis of the disease. Our aim was to study the effects of FGF-8b on proliferation of PC-3 prostate cancer cells and growth of PC-3 tumors, and to identify FGF-8b-associated molecular targets. Expression of ectopic FGF-8b in PC-3 cells caused a 1.5-fold increase in cell proliferation in vitro and a four- to fivefold increase in the size of subcutaneous and orthotopic prostate tumors in nude mice. Tumors expressing FGF-8b showed a characteristic morphology with a very rich network of capillaries. This was associated with increased spread of the cancer cells to the lungs as measured by RT-qPCR of FGF-8b mRNA. Microarray analyses revealed significantly altered, up- and downregulated, genes in PC-3 cell cultures (169 genes) and in orthotopic PC-3 tumors (61 genes). IPA network analysis of the upregulated genes showed the strongest association with development, cell proliferation (CRIP1, SHC1), angiogenesis (CCL2, DDAH2), bone metastasis (SPP1), cell-to-cell signaling and energy production, and the downregulated genes associated with differentiation (DKK-1, VDR) and cell death (CYCS). The changes in gene expression were confirmed by RT-qPCR. In conclusion, our results demonstrate that FGF-8b increases the growth and angiogenesis of orthotopic prostate tumors. The associated gene expression signature suggests potential mediators for FGF-8b actions on prostate cancer progression and metastasis.
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Proliferación Celular/efectos de los fármacos , Factor 8 de Crecimiento de Fibroblastos/farmacología , Neovascularización Patológica/inducido químicamente , Neoplasias de la Próstata/irrigación sanguínea , Animales , Línea Celular Tumoral , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica/patología , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/patología , Neoplasias de la Próstata/patologíaRESUMEN
Prostate cancer is the most common malignancy of men in Western countries. Patients with advanced prostate cancer suffer from incurable bone metastases. Recent data indicate that interactions between prostate cancer cells, osteoblasts, osteoclasts and the bone matrix are essential in the formation of bone metastases. FGF-8 is widely overexpressed in prostate cancer. Recently, FGF-8 has been found to affect both osteoblast and osteoclast differentiation. The aim of this study was to examine the role of FGF-8 in bone metastasis of prostate cancer. Immunohistochemistry was used to analyse FGF-8 expression in clinical samples of prostate cancer bone metastases. The functional significance of FGF-8 in growth of bone metastasis and formation of bone lesions was verified by using intratibial inoculations of FGF-8 or mock transfected PC-3 prostate cancer cells in nude mice. Intratibial tumors and bone lesions were analysed with X-ray, micro-CT and detailed histomorphometry using image analysis software and with immunostaining for osteocalcin and cathepsin K. Immunohistochemical analysis of tissue microarray of bone metastases of human prostate cancer showed that 76% of human bone metastasis samples (n = 25 from 11 patients) were positive for FGF-8. FGF-8 increased the growth of intratibial tumors and local formation of lytic and sclerotic lesions of bone. These results demonstrate that FGF-8 is expressed at a high frequency in bone metastases of human prostate cancer and that expression of FGF-8 in PC-3 prostate cancer cells increases their growth as intratibial tumors and modulates formation of bone lesions in an in vivo model of prostate cancer bone metastasis.
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Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Anciano , Animales , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Distribución Aleatoria , Transducción de Señal , Tibia/metabolismo , Tibia/patología , Regulación hacia ArribaRESUMEN
BACKGROUND: Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis. METHODS: PC-3 cells (5 x 10(5)) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry. RESULTS: Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm3, range: 96-485 mm3, n = 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm3, range: 209-1350 mm3, n = 13) (p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed. CONCLUSION: Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by decreased angiogenesis and increased apoptosis. The results suggest that bisphosphonates have anti-tumoral and anti-invasive effects on primary prostate cancer.
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Adenocarcinoma/secundario , Alendronato/uso terapéutico , Antineoplásicos/uso terapéutico , Metástasis Linfática/prevención & control , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/prevención & control , Alendronato/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/análisis , División Celular/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Neovascularización Patológica/tratamiento farmacológico , Neoplasias de la Próstata/patología , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Organismos Libres de Patógenos Específicos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: The aim of this follow-up study was to examine whether the legislative changes that took place in Finland in 2004 had an impact on the interactions between pharmaceutical companies and medical students. According to a previous survey, information provided by pharmaceutical companies represented one of the most important sources of information on pharmaceutical products for medical students and students frequently attended promotional events. METHODS: The authors collected the survey data using questionnaires distributed to medical students in Finland's five medical departments in spring 2005. A total of 1523 students (44% of all medical students in Finland) responded to the questionnaire. Results were compared with the findings of a previous study conducted in 2000. RESULTS: We found a dramatic drop in how often students attended promotions given by pharmaceutical company representatives (PCRs), with 17% versus 68% of students in the clinical phase of study attending at least twice a month (P < 0.001). Other educational events organised by pharmaceutical companies were attended by 3% versus 22% of clinical students (P < 0.001). In addition, presentations by PCRs and industry-sponsored educational events were not regarded as such important sources of information as they had been earlier and the perceived influence of promotion on future prescribing habits had decreased (12% versus 25% indicated that promotion influences prescribing; P < 0.001). Almost two-thirds of the students indicated that basic medical education should provide them with more efficient tools for critical assessment of the claims made by pharmaceutical marketing departments. CONCLUSIONS: Legislative reform has decreased the amount of contact between the pharmaceutical industry and medical students and diminished the role of industry-sponsored promotion as a source of information on pharmaceutical products.
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Actitud del Personal de Salud , Industria Farmacéutica/legislación & jurisprudencia , Servicios de Información sobre Medicamentos/legislación & jurisprudencia , Relaciones Interprofesionales , Estudiantes de Medicina/psicología , Adulto , Educación de Pregrado en Medicina/métodos , Femenino , Finlandia , Humanos , Legislación de Medicamentos , Masculino , Mercadotecnía/legislación & jurisprudencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Several members of the fibroblast growth factor (FGF) family have an important role in the development of skeletal tissues. FGF-8 is widely expressed in the developing skeleton, but its function there has remained unknown. We asked in this study whether FGF-8 could have a role in the differentiation of mesenchymal stem cells to an osteoblastic lineage. Addition of FGF-8 to mouse bone marrow cultures effectively increased initial cell proliferation as well as subsequent osteoblast-specific alkaline phosphatase production, bone nodule formation, and calcium accumulation if it was added to the cultures at an early stage of osteoblastic differentiation. Exogenous FGF-8 also stimulated the proliferation of MG63 osteosarcoma cells, which was blocked by a neutralizing antibody to FGF-8b. In addition, the heparin-binding growth factor fraction of Shionogi 115 (S115) mouse breast cancer cells, which express and secrete FGF-8 at a very high level, had an effect in bone marrow cultures similar to that of exogenous FGF-8. Interestingly, experimental nude mouse tumors of S115 cells present ectopic bone and cartilage formation as demonstrated by typical histology and expression of markers specific for cartilage (type II and IX collagen) and bone (osteocalcin). These results demonstrate that FGF-8 effectively predetermines bone marrow cells to differentiate to osteoblasts and increases bone formation in vitro. It is possible that FGF-8 also stimulates bone formation in vivo. The results suggest that FGF-8, which is expressed by a great proportion of malignant breast and prostate tumors, may, among other factors, also be involved in the formation of osteosclerotic bone metastases.