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2.
BMC Palliat Care ; 21(1): 188, 2022 Nov 02.
Article in English | MEDLINE | ID: mdl-36324132

ABSTRACT

BACKGROUND: The number of children and adolescents living with life-limiting conditions and potentially in need for specialised paediatric palliative care (SPPC) is rising. Ideally, a specialised multiprofessional team responds to the complex healthcare needs of children and their families. The questions of, how SPPC is beneficial, for whom, and under what circumstances, remain largely unanswered in the current literature. This study's overall target is to evaluate the effectiveness of a SPPC programme in Switzerland with respect to its potential to improve patient-, family-, health professional-, and healthcare-related outcomes. METHODS: This comparative effectiveness study applies a quasi-experimental design exploring the effectiveness of SPPC as a complex intervention at one treatment site in comparison with routine care provided in a generalised PPC environment at three comparison sites. As the key goal of palliative care, quality of life - assessed at the level of the patient-, the family- and the healthcare professional - will be the main outcome of this comparative effectiveness research. Other clinical, service, and economic outcomes will include patient symptom severity and distress, parental grief processes, healthcare resource utilisation and costs, direct and indirect health-related expenditure, place of death, and introduction of SPPC. Data will be mainly collected through questionnaire surveys and chart analysis. DISCUSSION: The need for SPPC has been demonstrated through numerous epidemiological and observational studies. However, in a healthcare environment focused on curative treatment and struggling with limited resources, the lack of evidence contributes to a lack of acceptance and financing of SPPC which is a major barrier against its sustainability. This study will contribute to current knowledge by reporting individual and child level outcomes at the family level and by collecting detailed contextual information on healthcare provision. We hope that the results of this study can help guiding the expansion and sustainability of SPPC and improve the quality of care for children with life-limiting conditions and their families internationally. TRIAL REGISTRATION: Registered prospectively on ClinicalTrials.gov on January 22, 2020. NCT04236180 PROTOCOL VERSION: Amendment 2, March 01, 2021.


Subject(s)
Hospice and Palliative Care Nursing , Palliative Care , Adolescent , Child , Humans , Delivery of Health Care , Outcome Assessment, Health Care , Palliative Care/methods , Quality of Life
3.
BMC Cancer ; 22(1): 254, 2022 Mar 09.
Article in English | MEDLINE | ID: mdl-35264144

ABSTRACT

BACKGROUND: The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification. METHODS: A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro. RESULTS: After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab. CONCLUSION: By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery. TRIAL REGISTRATION: Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Heparin-binding EGF-like Growth Factor/genetics , Hyaluronan Synthases/genetics , Proto-Oncogene Proteins/genetics , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Afatinib/pharmacology , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cetuximab/pharmacology , Drug Resistance, Neoplasm/genetics , Gene Expression/drug effects , Humans , Receptor, ErbB-2/drug effects , Trastuzumab/pharmacology
5.
BMC Cancer ; 20(1): 1039, 2020 Oct 28.
Article in English | MEDLINE | ID: mdl-33115415

ABSTRACT

BACKGROUND: Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. The molecular mechanisms of action for anti-HER-family drugs in gastric cancer cells are incompletely understood. We compared the molecular effects of trastuzumab and the other HER-family targeting drugs cetuximab and afatinib on phosphoprotein and gene expression level to gain insights into the regulated pathways. Moreover, we intended to identify genes involved in phenotypic effects of anti-HER therapies. METHODS: A time-resolved analysis of downstream intracellular kinases following EGF, cetuximab, trastuzumab and afatinib treatment was performed by Luminex analysis in the gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87. The changes in gene expression after treatment of the gastric cancer cell lines with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 h were analyzed by RNA sequencing. Significantly enriched pathways and gene ontology terms were identified by functional enrichment analysis. Furthermore, effects of trastuzumab and afatinib on cell motility and apoptosis were analyzed by time-lapse microscopy and western blot for cleaved caspase 3. RESULTS: The Luminex analysis of kinase activity revealed no effects of trastuzumab, while alterations of AKT1, MAPK3, MEK1 and p70S6K1 activations were observed under cetuximab and afatinib treatment. On gene expression level, cetuximab mainly affected the signaling pathways, whereas afatinib had an effect on both signaling and cell cycle pathways. In contrast, trastuzumab had little effects on gene expression. Afatinib reduced average speed in MKN1 and MKN7 cells and induced apoptosis in NCI-N87 cells. Following treatment with afatinib, a list of 14 genes that might be involved in the decrease of cell motility and a list of 44 genes that might have a potential role in induction of apoptosis was suggested. The importance of one of these genes (HBEGF) as regulator of motility was confirmed by knockdown experiments. CONCLUSIONS: Taken together, we described the different molecular effects of trastuzumab, cetuximab and afatinib on kinase activity and gene expression. The phenotypic changes following afatinib treatment were reflected by altered biological functions indicated by overrepresentation of gene ontology terms. The importance of identified genes for cell motility was validated in case of HBEGF.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Phosphoproteins/metabolism , Stomach Neoplasms/pathology , Afatinib/administration & dosage , Apoptosis , Biomarkers, Tumor/genetics , Cell Cycle , Cell Movement , Cell Proliferation , Cetuximab/administration & dosage , Gene Expression Profiling , Humans , Phenotype , Phosphoproteins/genetics , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Trastuzumab/administration & dosage , Tumor Cells, Cultured
6.
PLoS Comput Biol ; 16(3): e1007147, 2020 03.
Article in English | MEDLINE | ID: mdl-32119655

ABSTRACT

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a basis for the assessment of gastric cancer signaling and possibly for the development and discovery of predictive biomarkers.


Subject(s)
Cetuximab/pharmacology , Stomach Neoplasms/genetics , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/metabolism , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Cetuximab/genetics , Cetuximab/metabolism , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/metabolism , Humans , Models, Biological , Models, Statistical , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins/metabolism , R Factors , Signal Transduction/physiology , Stomach Neoplasms/drug therapy , ras Proteins/metabolism
7.
BMC Pediatr ; 18(1): 67, 2018 02 16.
Article in English | MEDLINE | ID: mdl-29452600

ABSTRACT

BACKGROUND: Paediatric end-of-life care is challenging and requires a high level of professional expertise. It is important that healthcare teams have a thorough understanding of paediatric subspecialties and related knowledge of disease-specific aspects of paediatric end-of-life care. The aim of this study was to comprehensively describe, explore and compare current practices in paediatric end-of-life care in four distinct diagnostic groups across healthcare settings including all relevant levels of healthcare providers in Switzerland. METHODS: In this nationwide retrospective chart review study, data from paediatric patients who died in the years 2011 or 2012 due to a cardiac, neurological or oncological condition, or during the neonatal period were collected in 13 hospitals, two long-term institutions and 10 community-based healthcare service providers throughout Switzerland. RESULTS: Ninety-three (62%) of the 149 reviewed patients died in intensive care units, 78 (84%) of them following withdrawal of life-sustaining treatment. Reliance on invasive medical interventions was prevalent, and the use of medication was high, with a median count of 12 different drugs during the last week of life. Patients experienced an average number of 6.42 symptoms. The prevalence of various types of symptoms differed significantly among the four diagnostic groups. Overall, our study patients stayed in the hospital for a median of six days during their last four weeks of life. Seventy-two patients (48%) stayed at home for at least one day and only half of those received community-based healthcare. CONCLUSIONS: The study provides a wide-ranging overview of current end-of-life care practices in a real-life setting of different healthcare providers. The inclusion of patients with all major diagnoses leading to disease- and prematurity-related childhood deaths, as well as comparisons across the diagnostic groups, provides additional insight and understanding for healthcare professionals. The provision of specialised palliative and end-of-life care services in Switzerland, including the capacity of community healthcare services, need to be expanded to meet the specific needs of seriously ill children and their families.


Subject(s)
Practice Patterns, Physicians'/statistics & numerical data , Terminal Care/methods , Adolescent , Child , Child, Preschool , Community Health Services/statistics & numerical data , Cross-Sectional Studies , Female , Hospitalization/statistics & numerical data , Humans , Infant , Infant, Newborn , Male , Palliative Care/statistics & numerical data , Pediatrics , Retrospective Studies , Switzerland , Terminal Care/statistics & numerical data
8.
Mol Oncol ; 12(4): 441-462, 2018 04.
Article in English | MEDLINE | ID: mdl-29325228

ABSTRACT

The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET-amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.


Subject(s)
Afatinib/pharmacology , Receptor, ErbB-2/metabolism , Stomach Neoplasms , Trastuzumab/pharmacology , Cell Line, Tumor , Enzyme Activation/drug effects , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/enzymology , Stomach Neoplasms/pathology
9.
BMC Cancer ; 17(1): 845, 2017 12 13.
Article in English | MEDLINE | ID: mdl-29237412

ABSTRACT

BACKGROUND: Gastric cancers frequently overexpress the epidermal growth factor receptor (EGFR), which has been implicated in pathological processes including tumor cell motility, invasion and metastasis. Targeting EGFR with the inhibitory antibody cetuximab may affect the motile and invasive behavior of tumor cells. Here, we evaluated the effects of EGFR signaling in gastric cancer cell lines to link the phenotypic behavior of the cells with their molecular characteristics. METHODS: Phenotypic effects were analyzed in four gastric cancer cell lines (AGS, Hs746T, LMSU and MKN1) by time-lapse microscopy and transwell invasion assay. Effects on EGFR signaling were detected using Western blot and proteome profiler analyses. A network was constructed linking EGFR signaling to the regulation of cellular motility. RESULTS: The analysis of the effects of treatment with epidermal growth factor (EGF) and cetuximab revealed that only one cell line (MKN1) was sensitive to cetuximab treatment in all phenotypic assays, whereas the other cell lines were either not responsive (Hs746T, LMSU) or sensitive only in certain tests (AGS). Cetuximab inhibited EGFR, MAPK and AKT activity and associated components of the EGFR signaling pathway to different degrees in cetuximab-sensitive MKN1 cells. In contrast, no such changes were observed in Hs746T cells. Thus, the different phenotypic behaviors of the cells were linked to their molecular response to treatment. Genetic alterations had different associations with response to treatment: while PIK3CA mutations and KRAS mutation or amplification were not obstructive, the MET mutation was associated with non-response. CONCLUSION: These results identify components of the EGFR signaling network as important regulators of the phenotypic and molecular response to cetuximab treatment.


Subject(s)
ErbB Receptors/metabolism , Signal Transduction/physiology , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Antineoplastic Agents, Immunological/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cetuximab/pharmacology , Humans , Neoplasm Invasiveness , Phenotype , Phosphorylation , Proteome/drug effects , Proteome/metabolism , Signal Transduction/drug effects
10.
J Cancer Res Clin Oncol ; 143(4): 573-600, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27933395

ABSTRACT

PURPOSE: Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab. METHODS: A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity. RESULTS: We found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab. CONCLUSIONS: Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Cetuximab/therapeutic use , Receptor, ErbB-2/metabolism , Stomach Neoplasms/drug therapy , Trastuzumab/therapeutic use , Amphiregulin/metabolism , Cell Division/drug effects , Cell Line, Tumor , Epidermal Growth Factor/metabolism , Heparin-binding EGF-like Growth Factor/metabolism , Humans , Ligands , Prognosis , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Transforming Growth Factor alpha/metabolism
11.
Med Image Anal ; 27: 72-83, 2016 Jan.
Article in English | MEDLINE | ID: mdl-25987193

ABSTRACT

In this paper we address the problem of recovering spatio-temporal trajectories of cancer cells in phase contrast video-microscopy where the user provides the paths on which the cells are moving. The paths are purely spatial, without temporal information. To recover the temporal information associated to a given path we propose an approach based on automatic cell detection and on a graph-based shortest path search. The nodes in the graph consist of the projections of the cell detections onto the geometrical cell path. The edges relate nodes which correspond to different frames of the sequence and potentially to the same cell and trajectory. In this directed graph we search for the shortest path and use it to define a temporal parametrization of the corresponding geometrical cell path. An evaluation based on 286 paths of 7 phase contrast microscopy videos shows that our algorithm allows to recover 92% of trajectory points with respect to the associated ground truth. We compare our method with a state-of-the-art algorithm for semi-automated cell tracking in phase contrast microscopy which requires interactively placed starting points for the cells to track. The comparison shows that supporting geometrical paths in combination with our algorithm allow us to obtain more reliable cell trajectories.


Subject(s)
Cell Tracking/methods , Image Interpretation, Computer-Assisted/methods , Microscopy, Phase-Contrast/methods , Microscopy, Video/methods , Pattern Recognition, Automated/methods , Stomach Neoplasms/pathology , Algorithms , Cell Line, Tumor , Cell Movement , Computer Simulation , Humans , Image Enhancement/methods , Models, Statistical , Reproducibility of Results , Sensitivity and Specificity , Signal Processing, Computer-Assisted , Signal-To-Noise Ratio , Spatio-Temporal Analysis , Stomach Neoplasms/physiopathology , Subtraction Technique
12.
Int J Oncol ; 41(2): 733-44, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22614881

ABSTRACT

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated in clinical studies. Reliable biomarkers for the identification of patients who are likely to benefit from this treatment are not available. In this study, we assessed the activity of cetuximab in five gastric cancer cell lines (AGS, AZ521, Hs746T, LMSU and MKN1). The viability of two of these cell lines, AZ521 and MKN1, was significantly reduced by cetuximab treatment. High expression and secretion levels of the EGFR-binding ligand, amphiregulin (AREG), were associated with cetuximab responsiveness. MET activation and mutations in Kirsten-Ras gene (KRAS) were associated with cetuximab resistance. By introducing a hierarchy between these markers, we established a model that facilitated the correct classification of all five gastric cancer cell lines as cetuximab responsive or non-responsive. The highest priority was allocated to activating KRAS mutations, followed by MET activation and finally by the levels of secreted AREG. In order to validate these results, we used three additional human gastric cancer cell lines (KATOIII, MKN28 and MKN45). In conclusion, we propose that our model allows the response of gastric cancer cell lines to cetuximab treatment to be predicted.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Glycoproteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Stomach Neoplasms/drug therapy , Amphiregulin , Antibodies, Monoclonal, Humanized , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor/drug effects , Cell Proliferation , Cell Survival/drug effects , Cetuximab , DNA Mutational Analysis , Drug Resistance, Neoplasm , EGF Family of Proteins , Enzyme Activation , Epidermal Growth Factor/metabolism , ErbB Receptors/metabolism , Humans , Mutation , Phosphorylation , Protein Processing, Post-Translational/drug effects , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-met/metabolism , Proto-Oncogene Proteins p21(ras) , ras Proteins/genetics
13.
J Manipulative Physiol Ther ; 35(3): 203-8, 2012.
Article in English | MEDLINE | ID: mdl-22386914

ABSTRACT

OBJECTIVE: The purposes of this study were to examine the range of thoracic spine extension motion in a group of young, asymptomatic subjects and compare the radiologically derived measurements with those obtained using photographic analysis, and to examine the relationship between the magnitude of the neutral thoracic kyphosis and the range of thoracic spine extension motion. METHODS: In 14 asymptomatic male subjects (mean age ± SD, 30.2 ± 7 years), the thoracic kyphosis in standing and full thoracic spine extension was measured from lateral thoracic spine radiographs and digital photographs. The difference between the 2 measurements was used to define the range of thoracic extension motion. RESULTS: The range of thoracic extension motion measured radiologically was between 0 and 26° (mean ± SD, 12.0° ± 8.9°), whereas the photographic range was between 8° and 23° (mean ± SD, 12.4° ± 4.1°). There was a significant correlation between the photographic and radiographic measurements of extension range (r = 0.69, P < .01). Extension range of motion measured radiologically was significantly correlated with the magnitude of the thoracic kyphosis (r = 0.71, P < .01). CONCLUSION: Functional radiographs of the thoracic spine can be used to measure the extension range of motion and define the extreme of range. The range of thoracic extension motion may be influenced by the magnitude of the neutral kyphosis. This technique may be used in future studies to evaluate the impact of spinal disorders on thoracic spine mobility.


Subject(s)
Kyphosis/diagnostic imaging , Photography/methods , Radiography, Thoracic/methods , Range of Motion, Articular/physiology , Thoracic Vertebrae/diagnostic imaging , Thoracic Vertebrae/physiology , Adult , Australia , Humans , Male , Motion , Reference Values , Reproducibility of Results , Sampling Studies , Spine/diagnostic imaging , Spine/physiology , Young Adult
14.
J Cancer Res Clin Oncol ; 138(5): 843-58, 2012 May.
Article in English | MEDLINE | ID: mdl-22290393

ABSTRACT

PURPOSE: The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated. Reliable biomarkers for the identification of patients who are likely to benefit from the treatment are not available. The aim of the study was to examine the drug sensitivity of five gastric cancer cell lines towards cetuximab as a single agent and to establish predictive markers for chemosensitivity in this cell culture model. The effect of a combination of cetuximab with chemotherapy was compared between a sensitive and a nonsensitive cell line. METHODS: EGFR expression, activation and localisation, the presence and subcellular localisation of the cell adhesion molecule E-cadherin as well as MET activation were examined by Western blot analysis, flow cytometry and immunofluorescence staining. Cells were treated with varying concentrations of cetuximab and cisplatin and 5-fluorouracil in tumour-relevant concentrations. The biological endpoint was cell viability, which was measured by XTT cell proliferation assay. Response to treatment was evaluated using statistical methods. RESULTS: We assessed the activity of cetuximab in five gastric cancer cell lines (AGS, KATOIII, MKN1, MKN28 and MKN45). The viability of two cell lines, MKN1 and MKN28, was significantly reduced by cetuximab treatment. High EGFR expression and low levels of receptor activation were associated with cetuximab responsiveness. MET activation as well as mutations of KRAS and CDH1 (gene encoding E-cadherin) was associated with cetuximab resistance. CONCLUSION: These data indicate that our examinations may be clinically relevant, and the candidate markers should therefore be tested in clinical studies.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cadherins/genetics , Gene Expression Regulation, Neoplastic/physiology , Proto-Oncogene Proteins c-met/metabolism , Proto-Oncogene Proteins/genetics , Stomach Neoplasms/drug therapy , ras Proteins/genetics , Antigens, CD , Biomarkers, Tumor , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Cetuximab , Cisplatin/pharmacology , Drug Resistance, Neoplasm , ErbB Receptors/metabolism , Flow Cytometry , Fluorescent Antibody Technique, Indirect , Fluorouracil/pharmacology , Humans , Mutation , Phosphorylation , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins p21(ras) , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism
15.
Eur J Public Health ; 21(3): 300-5, 2011 Jun.
Article in English | MEDLINE | ID: mdl-20478835

ABSTRACT

BACKGROUND: In the light of increasing childhood obesity, the role of food advertisements relayed on television (TV) is of high interest. There is evidence of food commercials having an impact on children's food preferences, choices, consumption and obesity. We describe the product categories advertised during kids programmes, the type of food promoted and the characteristics of food commercials targeting children. METHODS: A content analysis of the commercials aired during the kids programmes of six Swiss, one German and one Italian stations was conducted. The commercials were collected over a 6-month period in 2006. RESULTS: Overall, 1365 h of kids programme were recorded and 11 613 advertisements were found: 3061 commercials (26.4%) for food, 2696 (23.3%) promoting toys, followed by those of media, cleaning products and cosmetics. Regarding the broadcast food advertisements, 55% were for fast food restaurants or candies. CONCLUSION: The results of the content analysis suggest that food advertising contributes to the obesity problem: every fourth advertisement is for food, half of them for products high in sugar and fat and hardly any for fruit or vegetables. Long-term exposure to this distortion of the pyramid of recommended food should be considered in the discussion of legal restrictions for food advertising targeting children.


Subject(s)
Advertising , Child Nutritional Physiological Phenomena , Food , Obesity/etiology , Television , Child , Food Preferences , Germany , Humans , Italy , Nutrition Policy , Obesity/prevention & control , Switzerland
16.
AAOHN J ; 58(10): 437-44; quiz 435-6, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20954578

ABSTRACT

With the aging of the current nursing work force, nursing leaders must develop strategies to maintain current employment levels and improve availability of nurses to care for patients. One way to maintain current levels is to retain older nurses at the bedside by adapting the current working environment to meet the needs and the limitations associated with aging. This article includes a review of literature on the effects of aging on the human body, cognitively, physically, and psychosocially; current trends in the aging population; the advantages and disadvantages of employing aging nurses; retention strategies to keep aging nurses at the bedside; methods to adapt the work environment to aging nurses' needs; policies that address the needs of aging nurses; and implications for occupational health nursing practice. This article is limited to aging as it relates to nurses employed in hospitals.


Subject(s)
Aging/physiology , Nursing Staff, Hospital , Humans , Occupational Health , Personnel Staffing and Scheduling
18.
AAOHN J ; 57(12): 497-502; quiz 503-4, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20043622

ABSTRACT

It is estimated 1.3 million health care errors occur each year and of those errors 48,000 to 98,000 result in the deaths of patients (Barger et al., 2006). Errors occur for a variety of reasons, including the effects of extended work hours and shift work. The need for around-the-clock staff coverage has resulted in creative ways to maintain quality patient care, keep health care errors or adverse events to a minimum, and still meet the needs of the organization. One way organizations have attempted to alleviate staff shortages is to create extended work shifts. Instead of the standard 8-hour shift, workers are now working 10, 12, 16, or more hours to provide continuous patient care. Although literature does support these staffing patterns, it cannot be denied that shifts beyond the traditional 8 hours increase staff fatigue, health care errors, and adverse events and outcomes and decrease alertness and productivity. This article includes a review of current literature on shift work, the definition of shift work, error rates and adverse outcomes related to shift work, health effects on shift workers, shift work effects on older workers, recommended optimal shift length, positive and negative effects of shift work on the shift worker, hazards associated with driving after extended shifts, and implications for occupational health nurses.


Subject(s)
Health Personnel , Occupational Health , Personnel Staffing and Scheduling , Safety Management , Efficiency , Fatigue/epidemiology , Fatigue/prevention & control , Health Personnel/organization & administration , Humans , Medical Errors/prevention & control , Medical Errors/statistics & numerical data , Occupational Health Nursing , Sleep Disorders, Circadian Rhythm/epidemiology , Sleep Disorders, Circadian Rhythm/prevention & control , United States/epidemiology
19.
J Antibiot (Tokyo) ; 61(6): 356-64, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18667783

ABSTRACT

Bendigoles A approximately C are the first secondary metabolites to be isolated from a member of the actinomycete genus Gordonia. They were detected in a culture filtrate extract of Gordonia australis Acta 2299 by HPLC-diode array analysis and characterized as new steroids by mass spectrometry and NMR experiments. Bendigole C show binding affinity to the human progesterone and A approximately C to androgen receptor but are inactive at mineralocorticoid and estrogen receptors. In in vitro transactivation studies bendigoles A and C showed moderate and weak androgenic activities.


Subject(s)
Androgens , Androgens/biosynthesis , Gordonia Bacterium/metabolism , Hydroxysteroids/metabolism , Androgens/chemistry , Androgens/isolation & purification , Androgens/pharmacology , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Fermentation , Gordonia Bacterium/classification , Gordonia Bacterium/growth & development , Humans , Hydroxysteroids/chemistry , Hydroxysteroids/isolation & purification , Hydroxysteroids/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Progesterone/metabolism , Receptors, Androgen/metabolism , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Receptors, Mineralocorticoid/drug effects , Receptors, Mineralocorticoid/metabolism
20.
J Antibiot (Tokyo) ; 61(3): 158-63, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18503194

ABSTRACT

A family of three novel aminofuran antibiotics named as proximicins was isolated from the marine Verrucosispora strain MG-37. Proximicin A was detected in parallel in the marine abyssomicin producer "Verrucosispora maris" AB-18-032. The characteristic structural element of proximicins is 4-amino-furan-2-carboxylic acid, a hitherto unknown gamma-amino acid. Proximicins show a weak antibacterial activity but a strong cytostatic effect to various human tumor cell lines.


Subject(s)
Actinobacteria/metabolism , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/pharmacology , Netropsin/analogs & derivatives , Actinobacteria/chemistry , Actinobacteria/classification , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/isolation & purification , Antibiotics, Antineoplastic/biosynthesis , Antibiotics, Antineoplastic/isolation & purification , Bacteria/drug effects , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Fermentation , Humans , Microbial Sensitivity Tests , Netropsin/biosynthesis , Netropsin/isolation & purification , Netropsin/pharmacology , Spectrophotometry, Ultraviolet
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