963 resultados para TREATMENT-EXPERIENCED PATIENTS
Resumo:
The sizing of nursing human resources is an essential management tool to meet the needs of the patients and the institution. Regarding to the Intensive Care Unit, where the most critical patients are treated and the most advanced life-support equipments are used, requiring a high number of skilled workers, the use of specific indicators to measure the workload of the team becomes necessary. The Nursing Activities Score is a validated instrument for measuring nursing workload in the Intensive Care Unit that has demonstrated effectiveness. It is a cross-sectional study with the primary objective of assessing the workload of nursing staff in an adult Intensive Care Unit through the application of the Nursing Activities Score. The study was conducted in a private hospital specialized in the treatment of patients with cancer, which is located in the city of Natal (Rio Grande do Norte – Brazil). The study was approved by the Research Ethics Committee of the hospital (Protocol number 558.799; CAAE 24966013.7.0000.5293). For data collection, a form of sociodemographic characteristics of the patients was used; the Nursing Activities Score was used to identify the workload of nursing staff; and the instrument of Perroca, which classifies patients and provides data related to the their need for nursing care, was also used. The collected data were analyzed using a statistical package. The categorical variables were described by absolute and relative frequency, while the number by median and interquartile range. Considering the inferential approach, the Spearman test, the Wald chi-square, Kruskal Wallis and Mann-Whitney test were used. The statistically significant variables were those with p values <0.05. The evaluation of the overall averages of NAS, considering the first 15 days of hospitalization, was performed by the analysis of Generalized Estimating Equations (GEE), with adjust for the variable length of hospitalization. The sample consisted of 40 patients, in the period of June to August 2014. The results showed a mean age of 62,1 years (±23,4) with a female predominance (57,5%). The most frequent type of treatment was clinical (60,0%), observing an average stay of 6,9 days (±6,5). Considering the origin, most patients (35%) came from the Surgical Center. There was a mortality rate of 27,5%. 277 measures of NAS score and Perroca were performed, and the averages of 69,8% (±24,1) and 22,7% (±4.2) were obtained, respectively. There was an association between clinical outcome and value of the Nursing Activities Score in 24 hours (p <0.001), and between the degree of dependency of patients and nursing workload (rp 0,653, p<0,001). The achieved workload of the nursing staff, in the analyzed period, was presented high, showing that hospitalized patients required a high demand for care. These findings create subsidies for sizing of staff and allocation of human resources in the sector, in order to achieve greater safety and patient satisfaction as a result of intensive care, as well as an environment conducive to quality of life for the professionals
Resumo:
Kidney transplantation is the best treatment for patients who have lost kidney function. Renal transplant patients require accurate immunosuppressive drugs to prevent rejection. In this process T helper cells of the immune system perform key role in the immune response to the graft, and recently the Th17 cells has been investigated by production of IL-17 potent proinflammatory cytokine whose role in the rejection has also been described. Increased of Th17 cell expression has an important association with the development of rejection in renal microenvironment, however the likely mechanism is not well understood. This study aimed to evaluate the Th17 response from the influence of the chemotactic axis CCR6/CCL20 and genetic variants in IL-17 and IL-17RA. We conducted a case-control study involving 148 patients transplanted at the University Hospital Onofre Lopes/UFRN in which assessed by immunohistochemistry protein expression of IL-17 and chemokines CCR6/CCL20 and by PCR-RFLP genetic variants in IL17A and IL17RA. Our results showed no influence of genetic polymorphisms on the outcome of the graft or the protein expression of IL-17. In renal graft microenvironment found several sources producing IL-17: tubular epithelial cells, glomerular cells, neutrophils and cell interstitial infiltration, in turn the expression of chemotactic axis CCR6/CCL20 was restricted to the tubular epithelium cells. There was a slight positive linear correlation between the presence of IL-17 and expression of chemotactic axis CCR6/CCL20 in the microenvironment of renal graft. Therefore, we believe that, combined with our results, further studies with increased "n" sample and greater control over the variables involved in obtaining the renal specimen, can determine more clearly the influence of chemotactic axis CCR6 / CCL20 and polymorphisms in cytokines related to Th17 profile on the control of this cell subtype response in rejection processes to renal allograft.
Resumo:
New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1 -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1Amutant OCCC. Mol Cancer Ther; 15(7); 1472-84. Ó2016 AACR.
Resumo:
As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures cabazitaxel (Jevtana(®), Sanofi, UK) to submit evidence for the clinical and cost effectiveness of cabazitaxel for treatment of patients with metastatic hormone-relapsed prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the company's submission to NICE. Clinical evidence for cabazitaxel was derived from a multinational randomised open-label phase III trial (TROPIC) of cabazitaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone, which was assumed to represent best supportive care. The NICE final scope identified a further three comparators: abiraterone in combination with prednisone or prednisolone; enzalutamide; and radium-223 dichloride for the subgroup of people with bone metastasis only (no visceral metastasis). The company did not consider radium-223 dichloride to be a relevant comparator. Neither abiraterone nor enzalutamide has been directly compared in a trial with cabazitaxel. Instead, clinical evidence was synthesised within a network meta-analysis (NMA). Results from TROPIC showed that cabazitaxel was associated with a statistically significant improvement in both overall survival and progression-free survival compared with mitoxantrone. Results from a random-effects NMA, as conducted by the company and updated by the ERG, indicated that there was no statistically significant difference between the three active treatments for both overall survival and progression-free survival. Utility data were not collected as part of the TROPIC trial, and were instead taken from the company's UK early access programme. Evidence on resource use came from the TROPIC trial, supplemented by both expert clinical opinion and a UK clinical audit. List prices were used for mitoxantrone, abiraterone and enzalutamide as directed by NICE, although commercial in-confidence patient-access schemes (PASs) are in place for abiraterone and enzalutamide. The confidential PAS was used for cabazitaxel. Sequential use of the advanced hormonal therapies (abiraterone and enzalutamide) does not usually occur in clinical practice in the UK. Hence, cabazitaxel could be used within two pathways of care: either when an advanced hormonal therapy was used pre-docetaxel, or when one was used post-docetaxel. The company believed that the former pathway was more likely to represent standard National Health Service (NHS) practice, and so their main comparison was between cabazitaxel and mitoxantrone, with effectiveness data from the TROPIC trial. Results of the company's updated cost-effectiveness analysis estimated a probabilistic incremental cost-effectiveness ratio (ICER) of £45,982 per quality-adjusted life-year (QALY) gained, which the committee considered to be the most plausible value for this comparison. Cabazitaxel was estimated to be both cheaper and more effective than abiraterone. Cabazitaxel was estimated to be cheaper but less effective than enzalutamide, resulting in an ICER of £212,038 per QALY gained for enzalutamide compared with cabazitaxel. The ERG noted that radium-223 is a valid comparator (for the indicated sub-group), and that it may be used in either of the two care pathways. Hence, its exclusion leads to uncertainty in the cost-effectiveness results. In addition, the company assumed that there would be no drug wastage when cabazitaxel was used, with cost-effectiveness results being sensitive to this assumption: modelling drug wastage increased the ICER comparing cabazitaxel with mitoxantrone to over £55,000 per QALY gained. The ERG updated the company's NMA and used a random effects model to perform a fully incremental analysis between cabazitaxel, abiraterone, enzalutamide and best supportive care using PASs for abiraterone and enzalutamide. Results showed that both cabazitaxel and abiraterone were extendedly dominated by the combination of best supportive care and enzalutamide. Preliminary guidance from the committee, which included wastage of cabazitaxel, did not recommend its use. In response, the company provided both a further discount to the confidential PAS for cabazitaxel and confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in pre-prepared intravenous-infusion bags, which would remove the cost of drug wastage. As a result, the committee recommended use of cabazitaxel as a treatment option in people with an Eastern Cooperative Oncology Group performance status of 0 or 1 whose disease had progressed during or after treatment with at least 225 mg/m(2) of docetaxel, as long as it was provided at the discount agreed in the PAS and purchased in either pre-prepared intravenous-infusion bags or in vials at a reduced price to reflect the average per-patient drug wastage.
Resumo:
Bakgrund: Glaukom är en kronisk progressiv ögonsjukdom och en av den främsta orsaken till blindhet i världen. Intraockulärt trycksänkande ögondroppar är den vanligaste behandlingsmetoden och följsamhet är mycket viktigt för att minska progression av sjukdomen och risken att bli blind. Tidigare studier har visat att det finns en bristande följsamhet hos patienter med denna behandling. Syfte: Att belysa de faktorer som påverkar patientens följsamhet så att sjuksköterskan ska få en bättre förståelse och kunna vägleda patienten till en bättre följsamhet. Metod: En systematisk litteraturstudie genomfördes baserad på 14 vetenskapliga artiklar med både kvalitativ och kvantitativ ansats. Resultat: Det finns många olika faktorer som påverkar patientens följsamhet i behandlingen med ögondroppar. Det kan vara faktorer som är orsakade av sjukvårdspersonal, av patienten själv samt av miljö/socioekonomiska skäl. Slutsats: Det är viktigt att fortsätta forska på de faktorer som påverkar patienters följsamhet vid ögondroppsbehandling för att sjuksköterskan ska kunna vägleda till en ökad följsamhet.
Resumo:
The focus of this report is to enquire into and report on why people harm and kill themselves and to consider the role (including the limits of the role) that psychiatrists and other mental healthcare professionals play in their care and treatment. The experiences and views of people who harm themselves as well as those of their carers, health professionals and third-sector workers are central to this enquiry. As there is much policy and guidance on self-harm and suicide prevention, the report does not attempt to retrace this same ground but rather examines the evidence of practice on the ground, including the implementation of the National Institute for Health and Clinical Excellence (NICE) guidelines on self-harm (National Collaborating Centre for Mental Health, 2004). This report is the second in the Royal College of Psychiatristsââ,¬â"¢ programme of work on the broad issue of risk. The College report Rethinking Risk to Others was published in July 2008 (Royal College of Psychiatrists, 2008a) and a new Working Group was set up under the chairmanship of John, Lord Alderdice, to examine risk, self-harm and suicide. This clinical issue is an integral part of the role of the psychiatrist in ensuring the good care and treatment of patients. Our central theme is that the needs, care, well-being and individual human dilemma of the person who harms themselves should be at the heart of what we as clinicians do. Public health policy has a vital role to play and psychiatrists must be involved and not leave these crucial political and managerial decisions to those who are not professionally equipped to appreciate the complexities of self-harm and suicide. But we must never forget that we are not just dealing with social phenomena but with people who are often at, and beyond the limit of what they can emotionally endure. Their aggressive acts towards themselves can be difficult to understand and frustrating to address, but this is precisely why psychiatrists need to be involved to bring clarity to the differing causes for the self-destructive ways in which people act and to assist in managing the problems for the people concerned, including family, friends and professional carers, who sometimes find themselves at the end of their tether in the face of such puzzling and destructive behaviour.
Resumo:
BACKGROUND & AIMS: The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS: Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg.
Resumo:
Introdução: A Anorexia Nervosa (AN) é a perturbação do comportamento alimentar (PCA) com a maior taxa de mortalidade de todos os transtornos psiquiátricos. Carateriza-se pela recusa em manter um peso corporal normal mínimo, pela distorção da imagem corporal e por um obsessivo medo de ganhar peso. Os comportamentos patológicos a ela associados podem levar a uma semi-inanição que necessita de cuidados médicos pluridisciplinares, muitas vezes, em regime de internamento. Vários ensais clínicos avaliaram a eficácia da Terapia Cognitivo- Comportamental (TCC), indicando que ela favorece a remissão ou a diminuição da frequência de episódios de compulsão alimentar, dos comportamentos purgativos e da restrição alimentar. Objetivo: Combinar os resultados da melhor evidência científica de forma a avaliar a eficácia da TCC em comparação com outras terapias utilizadas no tratamento da AN. Métodos: A pesquisa realizou-se nas bases de dados eletrónicas da MEDLINE, Psyc-Info, Embase, CCTR e de forma manual, incluindo ensaios clínicos controlados randomizados que comparam a TCC com qualquer outro tipo de intervenção no tratamento da AN. Resultados: Foram incluídos 10 estudos que envolveram 957 pacientes: dos quais 571 (59,7%) foram submetidos a tratamento com Terapia cognitivo comportamental e 556 (49,3%) a outras terapias. Não se registaram diferenças significativas nos resultados obtidos em diversos outcomes, exceto nas subescalas Restrições (z=3,03; p=0,02), Preocupações alimentares (z=2,98; p=0,002) e Preocupações com a forma (z=1,71; p=0,09) do EDE e nos scores da escala GAF (z=1,87; p=0,06). Registaram-se diferenças estatisticamente significativas no número de episódios bulímicos (z=2,61; p=0,009), número de episódios de indução de vómito (z=2,11; p=0,03) e no número de episódios de uso indevido de laxantes (z=3,04; p=0,002). Conclusão: A utilização da Terapia Cognitivo-Comportamental no tratamento de doentes com AN parece melhorar bastante os sintomas da doença, revelando-se particularmente eficaz nos resultados obtidos na Eating Disorder Examination Scale. A sua utilização parece levar a uma melhoria no scores da GAF, evidenciando uma melhoria geral do estado de saúde dos pacientes (redução dos episódios de vómito, bulimia e uso de laxantes). / Página | viii ABSTRACT Background: Anorexia Nervosa is an eating disorder with the highest mortality rate of all psychiatric disorders. It is characterized by refusal to maintain a minimally normal body weight, the distortion of body image and obsessive fear of gaining weight. The pathological behaviors associated with it can lead to semi-starvation, requiring medical treatment and multidisciplinary inpatient care. Several clinical trials evaluated the efficacy of Cognitive Behavioral Therapy (CBT) in lead to remission or reduction of the frequency of bingue eating episodes, purgative behaviors and food restriction. Objective: Combining the results of the best scientific evidence to assess the efficacy of CBT in comparison with other therapies used in the treatment of AN. Methods: The research was carried out in electronic databases of MEDLINE, Psyc- Info, Embase, CCTR and manually, including randomized controlled trials that compared CBT with any other type of intervention in the treatment of AN. Results: Of which 571 (59.7%) were treated with cognitive behavioral therapy and 556 (49.3%) to other therapies: 10 studies involving 957 patients were included. No significant differences in the results obtained in different outcomes, except subscales Restrictions (z = 3.03, p = 0.02), Eating Concerns (z = 2.98, p = 0.002) and Shape Concerns (z = 1.71, p = 0.09) in the scores of EDE and the GAF scale (z = 1.87, p = 0.06). There were statistically significant differences in the number of bulimic episodes (z = 2.61, p = 0.009), number of episodes of induced vomiting (z = 2.11, p = 0.03) and the number of occurrences of use misuse of laxatives (z = 3.04, p = 0.002). Conclusion: The use of cognitive-behavioral therapy in the treatment of patients with AN seems to greatly improve the symptoms of the disease, revealing particularly effective results in the Eating Disorder Examination Scale. Its use seems to lead to an improvement in the GAF scores, showing a general improvement of the health status of patients (reduction of episodes of vomiting, bulimia and laxative use).
Resumo:
Hallux rígidus (HR) affects the first metatarsophalangeal joint (MTPJ) between 35% and 60% of the population over 65 years and there are multiple ways of treatment. Depending on the radiological stage where you find the deformity determines the procedure to be performed; in the early stages cheilectomy techniques and corrective osteotomy is performed while the more advanced ratings, the surgeon chooses destructive techniques considered as arthrodesis and arthroplasty. This final of degree project aims to focus on 1 MTPJ destructive techniques to clarify which of the procedures generates better results by a number of parameters; outcomes of the American Orthopaedic Foot scale and Ankle Society Hallux metatarsophalangeal Interphalangeal-scale (AOFAS), range of motion (ROM) of the 1ºAMTF, radiological classification. As for the implant arthroplasty technique, this article offers information on material and design that generates better relating to patient characteristics such as age, inflammatory joint diseases, viability and durability of the implant results. The conclusion from this review is that the values obtained in the arthrodesis according AOFAS decrease due to loss of mobility, but both techniques have similar values of effectiveness and concludes with the decision that the technique used is determined taking into account various factors and patient characteristics. Keywords: Hallux rígidus; (Hallux Rígidus) and surgery treatment; Hallux Rígidus arthrodesis; Hallux Rígidus arthroplasty; Hallux Rígidus (arthroplasty and arthrodesis).
Resumo:
O tratamento endodôntico é um procedimento comum em medicina dentária, tradicionalmente é realizado em múltiplas sessões, com medicação intracanalar entre sessões, para reduzir ou eliminar os microrganismos e os seus produtos antes da obturação, mas o conceito de tratamento numa sessão não é novo e nos últimos anos tem sido mais incorporado na prática clínica. O uso de técnicas endodônticas e equipamentos contemporâneos têm revolucionado os procedimentos endodônticos de modo a que seja possível a realização do tratamento endodôntico em uma única sessão, não só por aumentarem a taxa de sucesso do tratamento endodôntico, mas também por reduzirem o tempo necessário para o tratamento. A realização do tratamento numa única sessão tem vindo a ganhar aceitação como sendo o melhor tratamento na maioria dos casos, sendo que alguns endodontistas acreditam que existem poucos casos que não possam ser tratados com sucesso em uma única sessão. Dada a tendência para uma sociedade cada vez com um ritmo mais acelerado, este tipo de tratamento tem-se tornado o tratamento de eleição e habitualmente o tipo de tratamento preferido pelos pacientes Este trabalho tem como objetivo fazer uma revisão sobre o debate da realização do tratamento endodôntico em uma ou múltiplas sessões, avaliando todas as vantagens e desvantagens da realização do tratamento endodôntico numa sessão, comparativamente ao tratamento endodôntico em múltiplas sessões, bem como as suas indicações e contraindicações, de modo a proporcionar ao médico dentista uma informação atualizada desta abordagem clínica.
Resumo:
Antineoplastic drugs are hazardous chemical agents used mostly in the treatment of patients with cancer, however health professionals that handle and administer these drugs can become exposed and develop DNA damage. Comet assay is a standard method for assessing DNA damage in human biomonitoring and, combined with formamidopyrimidine DNA glycosylase (FPG) enzyme, it specifically detects DNA oxidative damage. The aim of this study was to investigate genotoxic effects in workers occupationally exposed to cytostatics (n = 46), as compared to a control group with no exposure (n = 46) at two Portuguese hospitals, by means of the alkaline comet assay. The potential of the OGG1 Ser326Cys polymorphism as a susceptibility biomarker was also investigated. Exposure was evaluated by investigating the contamination of surfaces and genotoxic assessment was done by alkaline comet assay in peripheral blood lymphocytes. OGG1 Ser326Cys (rs1052133) polymorphism was studied by Real Time PCR. As for exposure assessment, there were 121 (37%) positive samples out of a total of 327 samples analysed from both hospitals. No statistically significant differences (Mann-Whitney test, p > 0.05) were found between subjects with and without exposure, regarding DNA damage and oxidative DNA damage, nevertheless the exposed group exhibited higher values. Moreover, there was no consistent trend regarding the variation of both biomarkers as assessed by comet assay with OGG1 polymorphism. Our study was not statistically significant regarding occupational exposure to antineoplastic drugs and genetic damage assessed by comet assay. However, health professionals should be monitored for risk behaviour, in order to ensure that safety measures are applied and protection devices are used correctly.
Resumo:
The availability of a draft sequence for the human genome will revolutionise research into airway disease. This review deals with two of the most important areas impinging on the treatment of patients: pharmacogenetics and pharmacogenomics. Considerable inter-individual variation exists at the DNA level in targets for medication, and variability in response to treatment may, in part, be determined by this genetic variation. Increased knowledge about the human genome might also permit the identification of novel therapeutic targets by expression profiling at the RNA (genomics) or protein (proteomics) level. This review describes recent advances in pharmacogenetics and pharmacogenomics with regard to airway disease
Resumo:
Introdução: O tratamento ortodôntico tem como objetivo estabelecer uma oclusão funcionalmente e esteticamente estável e harmónica através de movimentos dentários apropriados. Estes movimentos estão fortemente relacionados com interações dentárias com os seus tecidos periodontais de suporte. Nos últimos anos, devido ao aumento do número de pacientes adultos que procuram tratamento ortodôntico, os ortodontistas frequentemente se deparam com pacientes com problemas periodontais. Assim, cabe ao profissional ter conhecimento das características da doença periodontal e suas sequelas bem como os efeitos, considerações e limitações do tratamento ortodôntico nos tecidos periodontais comprometidos. Objetivo: O objetivo deste trabalho foi realizar uma pesquisa bibliográfica de forma a verificar se o tratamento ortodôntico em pacientes com doença periodontal é possível sem agravar as condições periodontais, e sistematizar os pontos importantes a ter em conta para a realização do mesmo. Este tema torna-se importante uma vez que a procura de tratamento ortodôntico por parte de pacientes com problemas periodontais é cada vez mais frequente. Materiais e Métodos: Foi efetuada uma pesquisa bibliográfica de revisões sistemáticas, sendo aplicada uma limitação temporal de Janeiro de 2006 a Janeiro de 2016 e limitação linguística em inglês. Para a realização da mesma, utilizou-se o motor de busca MEDLINE/PubMed. Resultados: Foi possível constatar que o tratamento ortodôntico juntamente com a colaboração do paciente e ausência de inflamação periodontal pode conduzir a resultados satisfatórios sem causar danos irreversíveis para os tecidos periodontais. Além disso, o mesmo pode expandir as possibilidades de tratamento periodontal em certos pacientes.
Resumo:
Objectives: We report a fatal case of neuroleptic malignant-like syndrome, which occurred as a consequence of paralytic bowel in a 72-year-old woman on treatment with antiparkinson medication. Case description: Contrast enhanced computerized tomography of the chest and abdomen demonstrated the presence of paralytic bowel. Results: The patient died. Conclusions: Physicians involved in the treatment of patients affected by Parkinson’s disease should take into consideration the possibility of dopaminergic drug malabsorption due to paralytic bowel as a possible cause of neuroleptic malignant-like syndrome.
Resumo:
Abstract: The serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression. A previous analysis of colorectal tumors revealed that overexpression of splice variant Rac1b occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival. Patients with inflamed human colonic mucosa also have increased expression of Rac1b as well as mice with experimentally induced colitis. The increase of Rac1b in the mouse model was specifically prevented by the nonsteroidal anti-inflammatory drug ibuprofen. Purpose: The objective of our study is to understand the molecular regulation of Rac1b alternative splicing event and how it contributes to tumorigenesis. Experimental description: HT29 colorectal cell line was used as model to test several signaling pathways after 48h of treatment with ibuprofen. For this we analyzed the proteins of interest by Western Blot and the transcript levels by RT-PCR. Results: Mechanistic studies in cultured HT29 colorectal tumor cells revealed that ibuprofen inhibited Rac1b expression in a cyclooxygenase inhibition–independent manner and targets directly the alternative splicing event. Here, we provide evidence that ibuprofen leads to a decrease in expression of SRSF1, a splicing factor that we previously identified to promote Rac1b alternative splicing. Together, our results suggest that stromal cues, namely, inflammation, can trigger changes in Rac1b expression in the colon and identify ibuprofen as a highly specific and efficient inhibitor of Rac1b overexpression in colorectal tumors. Conclusions: Our data identify an additional cyclooxygenase–independent action of ibuprofen and suggest it may be beneficial in the treatment of patients with the subtype of BRAF-mutated serrated colorectal tumors.