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1.
Acta Oncol ; 60(7): 888-896, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33945383

RESUMO

Background: Inherited pathogenic variants (PVs) in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Carriers are at high risks to develop multiple primary melanomas and other cancers, in particular pancreatic cancer. In this study, the CDKN2A testing, carried out in Sweden in the years 2015-2020, was evaluated.Materials and methods: Included families had (1) three or more cases of melanoma and/or pancreatic cancer, (2) two melanomas in first-degree relatives, the youngest case <55 years or (3) individuals with three or more multiple primary melanomas, the first before the age of 55 years, and no other affected family members. The included families had at least one affected member that had been tested for CDKN2A PVs.Results: In total, 403 families were included, whereof 913 family members had been diagnosed with cutaneous melanoma and 129 with pancreatic cancer, 33 (8.2%) were found to have PVs in CDKN2A. Frequencies ranged from 0.9% in families with only two melanomas to 43.2% in families with three or more melanoma cases and pancreatic cancer (p < 0.001). The frequency of PVs ranged from 2.1% to 16.5% in families where the youngest case was ≥55 years or <35 years (p = 0.040). In families with or without CDKN2A PVs, 37.6% and 10.0% had melanoma cases that had died from melanoma, respectively (p < 0.001).Discussion: Significant differences were seen in the frequencies of CDKN2A PVs, dependent on numbers or age at diagnosis of melanomas and diagnoses of pancreatic cancers in the family. Further, melanoma cases belonging to families that tested positive for CDKN2A PVs had a significantly higher mortality. To summarize, the current evaluation shows that, with adequately selected criteria to guide genetic testing, CDKN2A PVs are identified at significant frequencies. Identification of carrier families is of importance to ensure that members are enrolled in a preventive surveillance program.


Assuntos
Melanoma , Neoplasias Cutâneas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes p16 , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Suécia/epidemiologia
2.
Cogn Technol Work ; 22(3): 667-683, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32834773

RESUMO

Resilience has in recent decades been introduced as a term describing a new perspective within the domains of disaster management and safety management. Several theoretical interpretations and definitions of the essence of resilience have been proposed, but less work has described how to operationalise resilience and implement the concept within organisations. This case study describes the implementation of a set of general resilience management guidelines for critical infrastructure within a Swedish Regional Medical Command and Control Team. The case study demonstrates how domain-independent guidelines can be contextualised and introduced at an operational level, through a comprehensive capability development programme. It also demonstrates how a set of conceptual and reflective tools consisting of educational, training and exercise sessions of increasing complexity and realism can be used to move from high-level guidelines to practice. The experience from the case study demonstrates the value of combining (1) developmental learning of practitioners' cognitive skills through resilience-oriented reflection and interaction with dynamic complex open-ended problems; (2) contextualisation of generic guidelines as a basis for operational methodological support in the operational environment; and (3) the use of simulation-based training as part of a capability development programme with increasing complexity and realism across mixed educational, training and exercise sessions. As an actual example of a resilience implementation effort in a disaster medicine management organisation, the study contributes to the body of knowledge regarding how to implement the concept of resilience in operational practice.

3.
Nurse Educ Today ; 55: 20-25, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28505521

RESUMO

INTRODUCTION: Head nurses at emergency departments often assume responsibility for managing the initial response to a major incident, and to create surge capacity. Training is essential to enable these nurses to perform an effective disaster response. Evaluating the effects of such training is however complicated as real skill only can be demonstrated during a real major incident. Self-efficacy has been proposed as an alternative measure of training effectiveness. PURPOSE: The aim of this study was to examine if short, small-scale computer-based simulation exercises could improve head emergency nurses' general and specific self-efficacy and initial incident management skills. METHOD: A within-group pretest-posttest design was used to examine 13 head nurses' general and specific self-efficacy before and after an intervention consisting of three short computer based simulation exercises during a 1-h session. Management skills were assessed using the computer simulation tool DigEmergo. RESULTS: The exercises increased the head nurses' general self-efficacy but not their specific self-efficacy. After completing the first two exercises they also exhibited improved management skills as indicated by shorter time to treatment for both trauma and in-hospital patients. CONCLUSION: This study indicates that short computer based simulation exercises provide opportunities for head nurses to improve management skills and increase their general self-efficacy.


Assuntos
Simulação por Computador , Serviço Hospitalar de Emergência , Incidentes com Feridos em Massa , Enfermeiros Administradores/educação , Autoeficácia , Adulto , Competência Clínica , Educação Continuada em Enfermagem , Feminino , Humanos , Masculino , Inquéritos e Questionários
4.
J Org Chem ; 74(24): 9265-73, 2009 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-19911774

RESUMO

A series of C,C-diacetylenic phosphaalkenes 1b-e has been prepared from 1-chloropenta-1,2-dien-4-ynes 6b-e in a reaction with Mes*PCl(2) (Mes* = 2,4,6-((t)Bu)(3)Ph) in the presence of LDA. Under identical conditions, isomeric butadiyne-substituted phosphaalkenes 2c-f can be obtained from 3-chloropenta-1,4-diynes 5c-f. The title compounds represent rare examples of diethynylethenes in which a constituting methylene has been replaced by a phosphorus center. The formation of both isomers can be rationalized by a common pathway that involves isomeric allenyllithium species. Spectroscopic, electrochemical, and theoretical investigations show that the phosphorus heteroatoms are an intrinsic part of the compounds' pi-systems and lead to decreased HOMO-LUMO gaps compared to those in all-carbon-based reference compounds.

5.
Biol Pharm Bull ; 31(6): 1192-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18520053

RESUMO

A vegetarian diet rich in phytochemicals may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Compounds passing the digestive system reaching the colon could potentially be detected in fecal water. We previously reported that intact fecal water samples from human volunteers significantly decreased prostaglandin production and COX-2 protein expression in colonic cells. The aim with the present study was to further study the composition of the fecal waters, using NMR spectroscopy and multivariate data analysis, and to trace the COX-2 inhibiting activity. Intact fecal water samples and fractions thereof were analyzed for their ability to inhibit prostaglandin E2 production in the human colon cell line HT-29. The majority of the tested aqueous phases derived from intact fecal water showed ability to inhibit prostaglandin production in cells (13.8+/-1.34% inhibition, p=0.01). NMR analysis indicated the presence of significant quantities of amino acids and fatty acids. Major metabolites included; acetic acid, butanoic acid, propanoic acid, glutamic acid and alanine. Smaller amounts of glycine and fumaric acid, which are known to have anti-inflammatory and anti-tumorigenic properties, were also detected. This study describes for the first time NMR metabolomic analysis of fecal water from subjects on a vegetarian diet.


Assuntos
Dieta Vegetariana , Fezes/química , Água/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/análise , Dinoprostona/metabolismo , Ácidos Graxos/metabolismo , Células HT29 , Humanos , Espectroscopia de Ressonância Magnética , Metabolismo , Anafilaxia Cutânea Passiva , Extratos de Tecidos/metabolismo , Extratos de Tecidos/farmacologia , Água/química
6.
Biol Pharm Bull ; 31(3): 534-7, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18310926

RESUMO

Many phytochemicals found in the diet may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Inflammation and subsequent elevation of the enzyme cyclooxygenase-2 (COX-2) are two such factors involved in the development of colon cancer, and inhibition of these processes could be important targets for chemoprevention. We have previously shown COX-2 inhibitory activity locally in the colon; e.g. in human fecal water from a group of vegetarians. In this study we focus on 2-pentanone, a frequently occurring compound in common foods such as banana and carrot. The aim was to study the inhibitory effects on prostaglandin production and COX-2 protein expression in tumour necrosis factor-alpha stimulated colon cancer cells (HT29) by radioimmunoassay and Western blotting. 2-Pentanone inhibited both prostaglandin production and COX-2 protein expression in human colon cancer cells. A concentration of 400 mumol/l 2-pentanone inhibited the prostaglandin production by 56.9+/-12.9% which is in the same range as the reference compound NS398 (59.8+/-7.6%). The two highest concentrations of 2-pentanone were further analyzed by Western blot, and 400 micromol/l and 200 micromol/l 2-pentanone resulted in a 53.3+/-9.6% and +/-27.1% reduction of the COX-2 protein levels respectively. Further studies on flavouring compounds, for example 2-pentanone, as colon cancer chemopreventives would be very valuable, and such results may contribute to future dietary recommendations.


Assuntos
Neoplasias do Colo/enzimologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/antagonistas & inibidores , Aromatizantes/farmacologia , Pentanonas/farmacologia , Western Blotting , Linhagem Celular Tumoral , Dieta Vegetariana , Relação Dose-Resposta a Droga , Humanos
8.
Biochem Biophys Res Commun ; 345(1): 260-70, 2006 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-16678133

RESUMO

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of apo alpha-lactalbumin and oleic acid, formed in casein after low pH treatment of human milk. This study examined if HAMLET-like complexes are present in casein from different species and if isolated alpha-lactalbumin from those species can form such complexes with oleic acid. Casein from human, bovine, equine, and porcine milk was separated by ion exchange chromatography and active complexes were only found in human casein. This was not explained by alpha-lactalbumin sequence variation, as purified bovine, equine, porcine, and caprine alpha-lactalbumins formed complexes with oleic acid with biological activity similar to HAMLET. We conclude that structural variation of alpha-lactalbumins does not preclude the formation of HAMLET-like complexes and that natural HAMLET formation in casein was unique to human milk, which also showed the highest oleic acid content.


Assuntos
Caseínas/química , Caseínas/farmacologia , Lactalbumina/química , Lactalbumina/farmacologia , Linfoma/patologia , Leite/química , Ácido Oleico/química , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Cavalos , Humanos , Camundongos , Dados de Sequência Molecular , Ácido Oleico/farmacologia , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Suínos
9.
Leuk Res ; 29(9): 1079-81, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16038735

RESUMO

The correlation between drug sensitivity in vitro and the mutation status of the FLT3 receptor gene was evaluated in tumour cells from 17 previously untreated AML patients. Tumour cells with internal tandem duplication (ITD) in the FLT3 receptor gene were significantly more sensitive to the FLT3 inhibitor SU5614 than tumour cells with wild type FLT3. Combinations of SU5614 with etoposide and amsacrine showed better effect (p<0.05) compared with the respective single drugs. Our results suggest that the FLT3 inhibitor SU5614 may have a therapeutic potential, especially in combination with other cytotoxic agents, in patients with FLT3-ITD positive AML.


Assuntos
Antineoplásicos/administração & dosagem , Indóis/farmacologia , Leucemia Mieloide/tratamento farmacológico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Doença Aguda , Humanos , Indóis/administração & dosagem , Leucemia Mieloide/patologia , Mutação Puntual , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Células Tumorais Cultivadas , Tirosina Quinase 3 Semelhante a fms
10.
J Nutr ; 135(5): 1299-303, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15867328

RESUMO

New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human alpha-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, alpha-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.


Assuntos
Anticarcinógenos , Lactalbumina/imunologia , Leite Humano/imunologia , Humanos , Imunidade Inata , Lactalbumina/química , Lactalbumina/farmacologia , Modelos Moleculares , Conformação Proteica , Desnaturação Proteica
11.
Protein Sci ; 12(12): 2805-14, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14627740

RESUMO

Proteins can adjust their structure and function in response to shifting environments. Functional diversity is created not only by the sequence but by changes in tertiary structure. Here we present evidence that lipid cofactors may enable otherwise unstable protein folding variants to maintain their conformation and to form novel, biologically active complexes. We have identified unsaturated C18 fatty acids in the cis conformation as the cofactors that bind apo alpha-lactalbumin and form HAMLET (human alpha-lactalbumin made lethal to tumor cells). The complexes were formed on an ion exchange column, were stable in a molten globule-like conformation, and had attained the novel biological activity. The protein-fatty acid interaction was specific, as saturated C18 fatty acids, or unsaturated C18:1trans conformers were unable to form complexes with apo alpha-lactalbumin, as were fatty acids with shorter or longer carbon chains. Unsaturated cis fatty acids other than C18:1:9cis were able to form stable complexes, but these were not active in the apoptosis assay. The results demonstrate that stereo-specific lipid-protein interactions can stabilize partially unfolded conformations and form molecular complexes with novel biological activity. The results offer a new mechanism for the functional diversity of proteins, by exploiting lipids as essential, tissue-specific cofactors in this process.


Assuntos
Lactalbumina/metabolismo , Lactalbumina/farmacologia , Metabolismo dos Lipídeos , Lipídeos/química , Dobramento de Proteína , Animais , Apoproteínas/química , Apoproteínas/metabolismo , Apoptose/efeitos dos fármacos , Cromatografia por Troca Iônica , Dicroísmo Circular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lactalbumina/química , Leucemia/patologia , Leucemia L1210 , Lipídeos/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Conformação Proteica , Espectrometria de Fluorescência , Especificidade por Substrato
12.
Adv Cancer Res ; 88: 1-29, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12665051

RESUMO

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of alpha-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET. This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.


Assuntos
Apoptose , Lactalbumina/uso terapêutico , Ácido Oleico/uso terapêutico , Transporte Ativo do Núcleo Celular , Animais , Sítios de Ligação , Cálcio/metabolismo , Diferenciação Celular , Citoplasma/metabolismo , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Humanos , Íons , Lipídeos , Transplante de Neoplasias , Conformação Proteica , Dobramento de Proteína , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo
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