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1.
Pain Med ; 23(11): 1828-1836, 2022 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-35652734

RESUMO

OBJECTIVE: Although there is growing interest in medically authorized cannabis for chronic pain, little is known about patients' perspectives. We explored perceptions of people living with chronic pain regarding benefits and concerns surrounding their use of cannabis for therapeutic purposes. SETTING: A hospital-based clinic in Hamilton and two community-based interdisciplinary pain clinics in Burlington, Ontario, Canada. METHODS: In this qualitative descriptive study, we conducted semi-structured interviews with 13 people living with chronic pain who used cannabis therapeutically, living in Ontario, Canada. We used thematic analysis, with data collection, coding, and analysis occurring concurrently. RESULTS: People living with chronic pain reported important benefits associated with use of cannabis for therapeutic purposes, including reduced pain, improved functionality, and less risk of harms compared to prescription opioids. Most patients also acknowledged harms, such as grogginess and coughing, and there was considerable variability in patient experiences. Financial costs and stigma were identified as important barriers to use of cannabis. CONCLUSION: Evidence-based guidance that incorporates patients' values and preferences may be helpful to inform the role of cannabis in the management of chronic pain.


Assuntos
Cannabis , Dor Crônica , Humanos , Dor Crônica/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Analgésicos/uso terapêutico , Pesquisa Qualitativa , Ontário
2.
Can Pharm J (Ott) ; 155(1): 50-59, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35035642

RESUMO

BACKGROUND: With the legalization of cannabis in Canada in 2018, pharmacists are increasingly likely to encounter patients using this substance. The primary objective of this pre-post questionnaire study was to evaluate the impact of an accredited cannabis course on the understanding, beliefs, perceptions and knowledge of undergraduate PharmD students. METHODS: A 38-question, web-based survey generated in REDCap was administered to third-year PharmD students at the University of Waterloo, prior to and right after taking an accredited cannabis course. The pre- and postsurvey data were analyzed using SPSS version 25. Pearson chi-square tests were performed on questions in which answers consisted of qualitative categorical data. Two-sided t tests were performed to test the significance of mean differences of questions measuring continuous variables. RESULTS: In a class of 120 students, 110 completed the presurvey and 79 students completed the postsurvey. After the course, students were more likely to report being knowledgeable and prepared for patient encounters dealing with medical and recreational cannabis, understanding that medical cannabis should be prescribed for select (vs all) medical conditions, rating the quality of evidence as poor to moderate for medical use of cannabis, understanding that medical documents should be more prescriptive and understanding that cannabis should not be sold in pharmacies (p < 0.05). INTERPRETATION: With cannabis education a part of their curriculum, pharmacy students felt more prepared to engage patients using cannabis both medically and recreationally. Furthermore, students were more cautious regarding the potential use of cannabis therapeutically and indicated that more oversight should be in place. Can Pharm J (Ott) 2021;154:xx-xx.

3.
BJU Int ; 123(1): 51-57, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29969172

RESUMO

OBJECTIVES: To train and compare machine-learning algorithms with traditional regression analysis for the prediction of early biochemical recurrence after robot-assisted prostatectomy. PATIENTS AND METHODS: A prospectively collected dataset of 338 patients who underwent robot-assisted prostatectomy for localized prostate cancer was examined. We used three supervised machine-learning algorithms and 19 different training variables (demographic, clinical, imaging and operative data) in a hypothesis-free manner to build models that could predict patients with biochemical recurrence at 1 year. We also performed traditional Cox regression analysis for comparison. RESULTS: K-nearest neighbour, logistic regression and random forest classifier were used as machine-learning models. Classic Cox regression analysis had an area under the curve (AUC) of 0.865 for the prediction of biochemical recurrence. All three of our machine-learning models (K-nearest neighbour (AUC 0.903), random forest tree (AUC 0.924) and logistic regression (AUC 0.940) outperformed the conventional statistical regression model. Accuracy prediction scores for K-nearest neighbour, random forest tree and logistic regression were 0.976, 0.953 and 0.976, respectively. CONCLUSIONS: Machine-learning techniques can produce accurate disease predictability better that traditional statistical regression. These tools may prove clinically useful for the automated prediction of patients who develop early biochemical recurrence after robot-assisted prostatectomy. For these patients, appropriate individualized treatment options can improve outcomes and quality of life.


Assuntos
Aprendizado de Máquina , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/cirurgia , Idoso , Área Sob a Curva , Previsões/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Prostatectomia/métodos , Recidiva , Análise de Regressão , Procedimentos Cirúrgicos Robóticos
4.
Anal Biochem ; 519: 8-14, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27940013

RESUMO

Measurement of free thiols in antibody therapeutics is important for product development and assessment of critical quality attributes. Earlier studies demonstrated fast separation of free thiol variants of IgG1 using reversed-phase high performance liquid chromatography (RP-HPLC) with diphenyl resin. Here, we report using N-tert-butylmaleimide (NtBM) alkylation followed by RP-HPLC and online mass spectrometry for rapid total and domain-specific free thiol characterization of IgG1. By increasing hydrophobicity, NtBM alkylation improves separation of free thiol variants from disulfide-linked main peak species. The unique mass shift by NtBM alkylation offers unambiguous characterization of free thiol variants by online mass spectrometry. Variant peaks separated by RP-HPLC were antibody molecules containing two NtBM-alkylated cysteines, corresponding to IgG1 containing two free thiols before alkylation. Further characterization of the collected fractions of variants by peptide mapping revealed that each variant contained unpaired cysteines located in specific IgG1 domains (CH1, CH3, VH and VL domains). Total molecular-level and domain-specific free thiol content measured by this method correlate well with orthogonal differential alkylation peptide mapping analysis, which measures free thiol level at individual cysteine residues. This method provides high throughput quantitation of total and domain-specific free thiol content in IgG1 molecules, facilitating rapid, comprehensive product and manufacturing process characterization.


Assuntos
Anticorpos Monoclonais/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Imunoglobulina G/química , Espectrometria de Massas/métodos , Compostos de Sulfidrila/química , Alquilação , Anticorpos Monoclonais/isolamento & purificação , Cisteína/química , Dissulfetos/química , Humanos , Imidas/química , Imunoglobulina G/isolamento & purificação , Mapeamento de Peptídeos
5.
J Adolesc ; 49: 60-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27007497

RESUMO

Researchers' understanding of bystanders' perspectives in the cyber-environment fails to take young people's perceptions into account and remains imperfect. Interventions encouraging adolescents to help targets of cyber-aggression are therefore typically based upon traditional school-based aggression research. Twenty-four in-depth interviews with Australian 13-16 year-olds revealed two themes that reflect how young bystanders perceive differences between aggression online and at school. The physical presence theme suggests that young bystanders struggle to determine online intentions in the absence of body language, leading to hesitancy in reactions and furthermore make it easier for them to ignore online transgressions and avoid becoming involved. The authority theme indicates young bystanders perceive that, compared to the school environment, the online environment lacks clearly established rules, authority figures and formal reporting mechanisms. These differences indicate that unique strategies should be developed to encourage young bystanders to intervene in cyber-aggression situations.


Assuntos
Bullying , Psicologia do Adolescente , Mídias Sociais , Adolescente , Agressão/psicologia , Feminino , Humanos , Masculino , Instituições Acadêmicas
6.
BMC Biol ; 10: 29, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22439642

RESUMO

BACKGROUND: There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. RESULTS: To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)γ inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease. CONCLUSIONS: We have established and validated a suite of highly reproducible tumor microplate three-dimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.


Assuntos
Antineoplásicos/farmacologia , Avaliação de Medicamentos/métodos , Células-Tronco Embrionárias/efeitos dos fármacos , Modelos Biológicos , Animais , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Furanos/farmacologia , Proteínas de Choque Térmico HSP90/farmacologia , Lactamas Macrocíclicas/farmacologia , Camundongos , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos
7.
Glob Implement Res Appl ; 3(1): 67-77, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37006595

RESUMO

The global workforce crisis significantly impacts how evidence-based treatment is provided to youth with developmental disabilities and co-occurring mental health conditions. Addressing the workforce crisis requires re-examining the long-standing methods of selecting individuals for employment based on academic degrees. This project offers an innovative workforce development option that provides specialized training to staff with advanced education degrees and staff with less education. The participants in this study were employed in a rural area of the USA within the mental health, child welfare, and correctional industries. All participants worked with youth experiencing intellectual disabilities and mental illness. Results indicated that participants improved their knowledge of the population, demonstrated a better understanding of EBPs, and were willing to employ evidence-based approaches regardless of their education or age. Although overall attitudes toward EBPs decreased, diverging attitudes increased, suggesting a need to accommodate treatment strategies when EBP models are unavailable for special populations. Initial knowledge gaps demonstrated by those with a master's degree and those with less education disappeared after the training. This finding supports the application of innovative task-shifting options in mental health, such as diverting more sophisticated care tasks to nonprofessionally trained persons, which can reduce workforce pressure and unmet demand for care. This study demonstrates cost-effective and time-efficient methods of training staff regardless of education by relying less on specific EBP models and more on adaptation.

8.
J Biol Chem ; 286(19): 16846-60, 2011 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-21385874

RESUMO

Voltage-gated sodium channel (VGSC) activity has previously been reported in endothelial cells (ECs). However, the exact isoforms of VGSCs present, their mode(s) of action, and potential role(s) in angiogenesis have not been investigated. The main aims of this study were to determine the role of VGSC activity in angiogenic functions and to elucidate the potentially associated signaling mechanisms using human umbilical vein endothelial cells (HUVECs) as a model system. Real-time PCR showed that the primary functional VGSC α- and ß-subunit isoforms in HUVECs were Nav1.5, Nav1.7, VGSCß1, and VGSCß3. Western blots verified that VGSCα proteins were expressed in HUVECs, and immunohistochemistry revealed VGSCα expression in mouse aortic ECs in vivo. Electrophysiological recordings showed that the channels were functional and suppressed by tetrodotoxin (TTX). VGSC activity modulated the following angiogenic properties of HUVECs: VEGF-induced proliferation or chemotaxis, tubular differentiation, and substrate adhesion. Interestingly, different aspects of angiogenesis were controlled by the different VGSC isoforms based on TTX sensitivity and effects of siRNA-mediated gene silencing. Additionally, we show for the first time that TTX-resistant (TTX-R) VGSCs (Nav1.5) potentiate VEGF-induced ERK1/2 activation through the PKCα-B-RAF signaling axis. We postulate that this potentiation occurs through modulation of VEGF-induced HUVEC depolarization and [Ca(2+)](i). We conclude that VGSCs regulate multiple angiogenic functions and VEGF signaling in HUVECs. Our results imply that targeting VGSC expression/activity could be a novel strategy for controlling angiogenesis.


Assuntos
Células Endoteliais/citologia , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Aorta/citologia , Cálcio/química , Diferenciação Celular , Eletrofisiologia/métodos , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Camundongos , Isoformas de Proteínas , RNA Interferente Pequeno/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia
9.
J Pharm Pract ; 35(2): 322-326, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33191836

RESUMO

BACKGROUND: Cannabidiol (CBD) serves as a promising medicine, with few known adverse effects apart from the potential of drug interactions with the cytochrome P450 system. It has been hypothesized drug interactions may occur with chemotherapeutic agents, but no supporting evidence has been published to date. CASE: A 58-year-old female with a history of bilateral breast carcinoma in remission, was treated with tamoxifen for breast cancer prevention for over 6 years. CBD was instituted to treat persistent postsurgical pain, inadequately managed by alternate analgesics. It was postulated that CBD may diminish tamoxifen metabolism by CYP3A4 and 2D6 to form active metabolite endoxifen, which exerts the anticancer benefits. Endoxifen, tamoxifen, N-desmetyltamoxifen and 4-hydroxytamoxifen levels were collected while the patient chronically received CBD 40 mg/day, and after a 60-day washout. Upon discontinuation of CBD 40 mg/day, it was observed that endoxifen levels increased by 18.75% and N-desmethyltamoxifen by 9.24%, while 4-hydroxytamoxifen remained unchanged. CONCLUSION: CBD at a low dose of 40 mg/day resulted in the potential inhibition of CYP3A4 and/or CYP2D6. Patients receiving CBD and interacting chemotherapeutic drugs, such as tamoxifen, require monitoring to identify possible subtherapeutic response to treatment. Further pharmacokinetic studies are required to ascertain the dynamics of this drug interaction.


Assuntos
Neoplasias da Mama , Canabidiol , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Canabidiol/uso terapêutico , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico
10.
PLoS One ; 17(4): e0266770, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35476678

RESUMO

Only a small proportion of COVID-19 patients in Canada have been recruited into clinical research studies. One reason is that few community intensive care units (ICUs) in Canada participate in research. The objective of this study was to examine the motivating factors, barriers and facilitators to research participation amongst Canadian community ICU stakeholders. A cross-sectional online survey was distributed between May and November 2020. The survey focused on 6 domains: participant demographics, ICU characteristics, ICU research infrastructure, motivating factors, perceived barriers, and perceived facilitators. Responses were received from 73 community ICU stakeholders, representing 18 ICUs. 7/18 ICUs had a clinical research program. Participants rated their interest in pandemic research at a mean of 5.2 (Standard Deviation [SD] = 1.9) on a 7-point Likert scale from 'not interested' to 'very interested'. The strongest motivating factor for research participation was the belief that research improves clinical care and outcomes. The most significant facilitators of research involvement were the availability of an experienced research coordinator and dedicated external funding to cover start-up costs, while the most significant barriers to research involvement were a lack of start-up funding for a research coordinator and a lack of ICU research experience. Canadian Community ICU stakeholders are interested in participating in pandemic research but lack basic infrastructure, research personnel, research experience and start-up funding. Evolution of a research support model at community hospitals, where most patients receive acute care, may increase research participation and improve the generalizability of funded research in Canada.


Assuntos
COVID-19 , COVID-19/epidemiologia , Canadá/epidemiologia , Estudos Transversais , Humanos , Unidades de Terapia Intensiva , Inquéritos e Questionários
11.
Can Urol Assoc J ; 15(6): E323-E328, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33212006

RESUMO

INTRODUCTION: Chronic pelvic pain (CPP) is a significant issue, and approximately 14% of women experience CPP once in their life-time. While interdisciplinary pain management is considered the gold standard of treatment, few programs offer this type of treatment in Canada. The aims of this paper were to: 1) describe the development of an interdisciplinary CPP program; and 2) demonstrate changes in patient-related outcomes after attending an interdisciplinary CPP program. METHODS: Referrals were received from community urologists and obstetricians/gynecologists, and pain physicians at the Michael G. DeGroote Pain Clinic. Patients attended an orientation session, completed an interdisciplinary assessment, and if appropriate, attended an eight-day interdisciplinary CPP program. Each day consisted of group-based pelvic floor physiotherapy, psychoeducation, goal-setting, cognitive behavioral therapy, and mindfulness. Psychometric questionnaires were completed pre- and post-program by patients, and paired sample t-tests were used to evaluate the changes in patient-related outcomes after attending the program. RESULTS: Thirty-seven female patients completed the program, and results demonstrate that the CPP program was associated with significant improvements in impact of pelvic pain on quality of life, readiness for change, and pain-related self-efficacy, as well as decreases in pain catastrophizing and fear of pain/re-injury. CONCLUSIONS: CPP is a complex condition that requires interdisciplinary management and care. The results of this study demonstrate the short-term benefits of an interdisciplinary CPP program, highlight the unique needs of women with CPP, and implicate multiple factors for programming and treatment.

12.
Pharm Pract (Granada) ; 18(4): 2088, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343771

RESUMO

OBJECTIVE: The primary objectives of this pre-post session study, was to evaluate the impact of a pharmacist-led education session on the perceived benefits and safety of cannabis among patients with chronic pain, as well as determine the influence of pharmacist education on the selection of safer cannabis products and dosage forms for medical use among patients. METHODS: A retrospective analysis of completed pre-post session questionnaires was conducted among chronic pain patients attending a mandatory education session led by a pharmacist, prior to being authorized cannabis in clinic. All questionnaire data was analyzed using SPSS v. 25. Demographic and sample characteristics were reviewed using univariate analyses. Chi-Square tests were employed to determine if the group-based education significantly affected knowledge, perception of efficacy and safety of cannabis. RESULTS: Of the 260 session participants, 203 completed pre-post session questionnaires. After the session, a majority of current cannabis users (33.8%) and cannabis naïve/past users (56.9%) reported they would use a low THC product in the future, and a majority of current users (54.5%) would use a high CBD product in the future. After education, participants were more likely to report cannabis as having the potential for addiction (chi-square =42.6, p <0.0001) and harm (chi-square =34.0, p <0.0001). CONCLUSIONS: Pharmacist counselling and education has the potential to influence patient selection and use of cannabis, from more harmful to safer products, as well as moderate the potential perceived benefits of use.

13.
Methods Mol Biol ; 467: 159-81, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19301670

RESUMO

This chapter covers the breakdown of the process of angiogenesis into simple assays to measure discrete endothelial cell functions. The techniques described are suitable for studying stimulators or inhibitors of angiogenesis and determining which aspect of the process is modulated. The procedures outlined are robust and straightforward but cannot cover the complexity of the angiogenic process as a whole, incorporating as it does myriad positive and negative signals, three-dimensional interactions with host tissues and many accessory cells, including fibroblasts, macrophages, pericytes, and platelets. The extent to which in vitro assays predict responses in vivo (e.g., wound healing, tumor angiogenesis, or surrogate techniques such as Matrigel plugs, sponge implants, corneal assays, etc.) remains to be determined.


Assuntos
Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Movimento Celular , Células Endoteliais/citologia , Células Endoteliais/enzimologia , Neovascularização Patológica , Peptídeo Hidrolases/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Humanos
14.
Bioorg Med Chem ; 17(8): 3169-76, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19303309

RESUMO

Phospholipase C-gamma (PLC-gamma) has been identified as a possible biological target for anticancer drug therapy but suitable inhibitors are lacking. Therefore, in order to identify active compounds (hits) virtual high throughput screening was performed. The crystal structure of the PLC-delta isoform was used as a model docking scaffold since no crystallographic data are available on its gamma counterpart. A pilot screen was performed using approximately 9.2x10(4) compounds, where the robustness of the methodology was tested. This was followed by the main screening effort where approximately 4.4x10(5) compounds were used. In both cases, plausible compounds were identified (virtual hits) and a selection of these was experimentally tested. The most potent compounds were in the single digit micro-molar range as determined from the biochemical (Flashplate) assay. This translated into approximately 15 microM in a functional assay in cells. About 30% of the virtual hits showed activity against PLC-gamma (IC(50)<50 microM).


Assuntos
Inibidores Enzimáticos/química , Fosfolipase C gama/antagonistas & inibidores , Sequência de Aminoácidos , Linhagem Celular Tumoral , Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Especificidade por Substrato
15.
Cancer Res ; 67(16): 7907-16, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17699797

RESUMO

Syk, a non-receptor tyrosine kinase, is an important component of immunoreceptor signaling in hematopoietic cells. It has been implicated in key regulatory pathways including phosphoinositide 3-kinase and phospholipase Cgamma (PLCgamma) activation in B cells and integrin signaling in platelets and bronchial epithelial cells. Recently, potential roles in cancer have been reported. In breast cancers, reduced Syk expression was associated with invasion, and its overexpression in cell lines was shown to inhibit cell motility. In contrast, Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. Its role in squamous cell carcinomas of the head and neck (SCCHN) has not yet been investigated. Syk mRNA and protein expression was detected in 6 of 10 SCCHN cell lines. When Syk was transfected into Syk-negative cells (SIHN-011A), chemomigration was enhanced in vitro and this was associated with activation of PLCgamma1. Conversely, abrogation of Syk activity by pharmacologic inhibition or small interfering RNA in HN6 cells with high levels of endogenous expression inhibited migration, haptotaxis, and engagement with matrix proteins; this was accompanied by decreased levels of phosphorylated AKT. Similar effects were seen in Syk-positive CAL 27 cells but not in Syk-negative SIHN-011A cells. Immunoprecipitation suggested co-association of Syk with epidermal growth factor receptor and GRB-2. Syk expression in SCCHN patient tissues was examined by semiquantitative real-time PCR (n = 45) and immunohistochemistry (n = 38) in two independent cohorts. Higher levels of Syk expression were observed in tumors and lymph node metastases relative to normal tissues. High Syk expression significantly correlated with worse survival and may be of prognostic value in SCCHN due to its potential role in cell migration and invasion.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Movimento Celular/fisiologia , Neoplasias de Cabeça e Pescoço/enzimologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Quimiotaxia , Progressão da Doença , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/biossíntese , Proteínas Tirosina Quinases/genética , Transdução de Sinais , Quinase Syk , Transfecção
16.
Cancer Res ; 67(12): 5840-50, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17575152

RESUMO

Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110alpha (2 nmol/L), p110beta (3 nmol/L), p110delta (3 nmol/L), and p110gamma (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 micromol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic.


Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Citometria de Fluxo , Humanos , Immunoblotting , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cancer Res ; 67(5): 2206-16, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17332351

RESUMO

The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting molecular target. Derivatives of the natural product geldanamycin, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), were the first HSP90 ATPase inhibitors to enter clinical trial. Synthetic small-molecule HSP90 inhibitors have potential advantages. Here, we describe the biological properties of the lead compound of a new class of 3,4-diaryl pyrazole resorcinol HSP90 inhibitor (CCT018159), which we identified by high-throughput screening. CCT018159 inhibited human HSP90beta with comparable potency to 17-AAG and with similar ATP-competitive kinetics. X-ray crystallographic structures of the NH(2)-terminal domain of yeast Hsp90 complexed with CCT018159 or its analogues showed binding properties similar to radicicol. The mean cellular GI(50) value of CCT018159 across a panel of human cancer cell lines, including melanoma, was 5.3 mumol/L. Unlike 17-AAG, the in vitro antitumor activity of the pyrazole resorcinol analogues is independent of NQO1/DT-diaphorase and P-glycoprotein expression. The molecular signature of HSP90 inhibition, comprising increased expression of HSP72 protein and depletion of ERBB2, CDK4, C-RAF, and mutant B-RAF, was shown by Western blotting and quantified by time-resolved fluorescent-Cellisa in human cancer cell lines treated with CCT018159. CCT018159 caused cell cytostasis associated with a G(1) arrest and induced apoptosis. CCT018159 also inhibited key endothelial and tumor cell functions implicated in invasion and angiogenesis. Overall, we have shown that diaryl pyrazole resorcinols exhibited similar cellular properties to 17-AAG with potential advantages (e.g., aqueous solubility, independence from NQO1 and P-glycoprotein). These compounds form the basis for further structure-based optimization to identify more potent inhibitors suitable for clinical development.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Compostos Heterocíclicos com 2 Anéis/farmacologia , Pirazóis/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Modelos Biológicos , Modelos Moleculares , Ligação Proteica , Pirazóis/química , Especificidade por Substrato , Células Tumorais Cultivadas
18.
Can J Pain ; 3(1): 70-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-35005395

RESUMO

Background: One in five Canadians experience chronic pain, and interdisciplinary pain programs are well established as the gold standard of treatment. However, not all patients are ready to engage in interdisciplinary treatment for chronic pain. Aims: The aims of this study were to (1) first demonstrate changes in patient-related outcomes after attending a publicly funded 8-week interdisciplinary pain program and (2) evaluate pain-related predictors of readiness for change. Methods: The institution's research ethics board approved this study. One hundred twenty-nine patients completed questionnaires on the first and last day of attending the program. Paired sample t-tests were utilized to evaluate the changes in patient-related outcomes after attending the program, and linear regressions were utilized to evaluate pain-related predictors of the stages of change. Results: Postprogram, there were significant decreases in pain-related interference, fear of pain/re-injury, pain catastrophizing, and symptoms of stress, depression, and anxiety and a significant increase in wellness-focused coping and self-efficacy. Postprogram, patients also demonstrated lower scores in precontemplation and contemplation and higher scores in action and maintenance stages of readiness for change. In predicting precontemplation, fear of pain/re-injury was the sole predictor, and self-efficacy was the sole predictor of the contemplation, action, and maintenance stages. Conclusion: These results demonstrate the short-term benefits of an 8-week interdisciplinary pain program. It is suggested that preprogram interventions targeting kinesophobia for individuals who are precontemplative and self-efficacy for others may be important to facilitate patient engagement.


Contexte: Un Canadien sur cinq souffre de douleur chronique. Il est bien établi que les programmes interdisciplinaires de la douleur constituent le traitement de référence. Toutefois, ce ne sont pas tous les patients qui sont prêts à suivre un traitement interdisciplinaire pour la douleur chronique.Buts: Les buts de cette étude étaient : 1) démontrer les changements dans les résultats liés aux patients après que ces derniers aient participé à un programme interdisciplinaire de la douleur de huit semaines, financé par des fonds publics, et 2) évaluer les prédicteurs de la disposition au changement lié à la douleur.Méthodes: La commission d'éthique de la recherche de l'institution a approuvé cette étude. Cent vingt-neuf patients ont répondu à des questionnaires le premier et le dernier jour de leur participation au programme. Des tests T pour échantillons appariés ont été utilisés pour évaluer les changements dans les résultats liés aux patients après avoir participé au programme et des régressions linéaires ont été utilisées pour évaluer les prédicteurs des étapes du changement lié à la douleur.Résultats: Après le programme, des diminutions significatives ont été observées dans l'interférence liée à la douleur, la peur de la douleur ou d'une nouvelle blessure, la catastrophisation de la douleur, ainsi que dans les symptômes de stress, de dépression, et d'anxiété. Une augmentation significative des stratégies d'adaptatation axées sur le bien-être et l'efficacité personnelle a aussi été observée. Après le progamme, les patients ont aussi obtenu des scores plus faibles pour la pré-contemplation et la contemplation et des scores plus élevés pour les étapes d'action et de mantien de la disposition au changement. La peur de la douleur ou d'une nouvelle blessure était l'unique prédicteur pour la pré-contemplation et l'efficacité personnelle était l'unique prédicteur des étapes de la contemplation, de l'action et du maintien.Conclusion: Ces résultats démontrent les bienfaits à court terme d'un programme interdisciplinaire de la douleur de huit semaines. Il est suggéré que les interventions pré-programme ciblant la kinésophobie, pour les individus qui sont à l'étape de la pré-contemplation, et l'efficacité personnelle pour d'autres, peuvent être importants pour faciliter l'engagement des patients.

19.
Lang Speech Hear Serv Sch ; 50(3): 399-415, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31283423

RESUMO

Purpose Children who are deaf and hard of hearing (DHH) face a wide array of issues that can impact their mental health and well-being. This study aimed to explore the role of schools and classroom teachers in supporting the mental health and well-being of DHH children. Method A qualitative study comprising telephone and semistructured interviews with 12 mainstream school classroom teachers who directly support the education and well-being of DHH children was conducted. Thematic analysis was used to analyze the data. Result Classroom teachers indicated they play an important role in supporting the mental health and well-being of DHH children but identified a range of constraints to providing this support. Four themes were identified: (a) "culture of professional practice," (b) "operationalized practice," (c) "constraints to practice," and (d) "solutions for constraints." Conclusions Classroom teachers play an important role in supporting the mental health and well-being of DHH children but face several constraints in their practice, including limited training and awareness and access to resources. While further research is needed, this study suggests that classroom resources and teacher professional development are needed to enhance classroom teachers' understanding of how to support the mental health and well-being of DHH children.


Assuntos
Educação de Pessoas com Deficiência Auditiva/métodos , Saúde Mental , Pessoas com Deficiência Auditiva/psicologia , Professores Escolares/psicologia , Adulto , Atitude Frente a Saúde , Criança , Compreensão , Feminino , Perda Auditiva/reabilitação , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Instituições Acadêmicas
20.
Am Surg ; 84(5): 652-657, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29966564

RESUMO

In 2010, 2.5 million people sustained a traumatic brain injury (TBI), with an estimated 75 per cent being mild TBI. Mild TBI is defined as a Glasgow Coma Scale (GCS) of 13 to 15. Based on recent data and our institutional experience, we hypothesized that mild TBI patients, including patients on aspirin, could be safely managed by trauma surgeons without neurosurgical consultation. Trauma patients admitted to a single Level I trauma center from June 2014 through July 2015 aged 18 years or older were evaluated. Patients with a GCS ≥14, regardless of intoxication, with an epidural or subdural hematoma ≤4 mm, trace or small subarachnoid hemorrhage, and/or nondisplaced skull fracture were prospectively enrolled. The primary outcomes were needed for neurosurgical consultation and intervention. Secondary outcomes included readmission rate and neurologic morbidity and mortality rate. Of 1341 trauma admits, 77 were enrolled. No patients required neurosurgical intervention. Only 1/75 (1.3%) patients required neurosurgical consultation. Outpatient follow-up was achieved with 75/77 (97.4%) patients. No mortalities, major neurologic morbidities, or readmissions were observed (95% confidence interval 0-4%). None of the 21 patients on aspirin required neurosurgical intervention and only 1/21 (4.8%) patients required neurosurgical consultation with no mortalities observed at follow-up. Management of mild TBI can be safely accomplished by trauma surgeons without routine neurosurgical consultation. Larger multicenter prospective studies are required to evaluate our finding that this also may be safe in patients taking aspirin.


Assuntos
Concussão Encefálica/diagnóstico , Concussão Encefálica/terapia , Encaminhamento e Consulta , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Concussão Encefálica/mortalidade , Protocolos Clínicos , Feminino , Seguimentos , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Neurocirurgia , Procedimentos Neurocirúrgicos , Readmissão do Paciente/estatística & dados numéricos , Estudos Prospectivos , Traumatologia , Adulto Jovem
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