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1.
Nucl Med Biol ; 110-111: 10-17, 2022.
Article in English | MEDLINE | ID: mdl-35468342

ABSTRACT

PURPOSE: The pO2 threshold of an ideal PET hypoxia tracer for radiotherapy planning in cancer would match those observed in clinically and biologically relevant processes such as radioresistance and HIF1α expression. To identify such tracers, we directly compared uptake in vitro of hypoxia PET tracers ([18F]FMISO, [64Cu]CuATSM, and analogues [64Cu]CuATS, [64Cu]CuATSE, [64Cu]CuCTS, [64Cu]CuDTS, [64Cu]CuDTSE, [64Cu]CuDTSM) with levels of radioresistance and HIF1α expression in cultured cancer cells under identical hypoxic conditions ranging from extreme hypoxia to normoxia. Pimonidazole uptake was also compared as a marker of hypoxia. METHODS: A custom-built hypoxia apparatus enabled all experiments to be performed under identical hypoxic conditions with constant measurement of pO2 in media using an OxyLab pO2™ probe. HCT116 human colonic carcinoma and MCF-7 human Caucasian breast adenocarcinoma cells were irradiated using a cobalt teletherapy unit. Clonogenic assays were used to assess survival. HIF1α expression was determined by western blotting, tracer uptake by gamma counting and pimonidazole binding by flow cytometry. RESULTS: Radioresistance, pimonidazole binding and HIF1α expression increased gradually as pO2 decreased between 25 mmHg and 0 mmHg. In contrast, all the PET hypoxia tracers showed a sharp increase in uptake only when pO2 levels fell below 1 mmHg. Above this threshold, tracer uptake was not elevated above that in normoxic cells. CONCLUSION: This study highlights an important mismatch in pO2 thresholds between these PET tracers and other markers of hypoxia: tracer uptake only occurred at oxygen levels that were well below levels that induced radioresistance, pimonidazole uptake and HIF1α expression. Although their pO2 thresholds do not match the threshold for resistance to conventionally fractionated radiotherapy (pO2 2.5-10 mmHg), their specificity for extreme hypoxia (pO2 ≪ 1 mmHg) suggests these PET tracers may be of particular use to predict outcomes in stereotactic radiation therapy where these maximally resistant cells play a key role in determining the biological effect.


Subject(s)
Neoplasms , Radiosurgery , Biomarkers , Cell Hypoxia , Humans , Hypoxia , Neoplasms/diagnostic imaging , Neoplasms/radiotherapy , Positron-Emission Tomography
3.
Support Care Cancer ; 28(2): 747-753, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31144173

ABSTRACT

PURPOSE: To determine the level of recall, satisfaction, and perceived benefits of early mobility (EM) among ventilated cancer patients after extubation in the intensive care unit (ICU). METHODS: A survey of patients' perceptions and recollections of EM was administered within 72 h of extubation. Data on recall of EM participation, activities achieved, adequacy of staffing and rest periods, strength to participate, activity level of difficulty, satisfaction with staff instructions, breathing management, and overall rating of the experience were analyzed. The Confusion Assessment Method for ICU (CAM-ICU) was used for delirium screening. RESULTS: Fifty-four patients comprised the study group. Nearly 90% reported satisfaction with instructions, staffing, rest periods, and breathing management during EM. Participants indicated that EM maintained their strength (67%) and gave them control over their recovery (61%); a minority felt optimistic (37%) and safe (22%). Patients who achieved more sessions and "out-of-bed" exercises had better recall of actual activities compared with those who exercised in bed. Overall, patients with CAM-ICU-positive results (33%) performed less physical and occupational therapy exercises. CONCLUSIONS: Ventilated cancer patients reported an overall positive EM experience, but factual memory impairment of EM activities was common. These findings highlight the needs and the importance of shaping strategies to deliver a more patient focused EM experience.


Subject(s)
Airway Extubation/psychology , Exercise Therapy/methods , Exercise Therapy/psychology , Exercise/psychology , Respiration, Artificial/psychology , Adult , Female , Humans , Intensive Care Units , Male , Memory Disorders/physiopathology , Middle Aged , Neoplasms , Pilot Projects , Range of Motion, Articular/physiology , Surveys and Questionnaires
4.
Nucl Med Commun ; 40(6): 611-617, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30893213

ABSTRACT

PURPOSE: Treatment of metastatic colorectal cancer frequently includes antiangiogenic agents such as bevacizumab. Size measurements are inadequate to assess treatment response to these agents, and newer response assessment criteria are needed. We aimed to evaluate F-FDG PET-derived texture parameters in a preclinical colorectal cancer model as alternative metrics of response to treatment with bevacizumab. MATERIALS AND METHODS: Fourteen CD1 athymic mice injected in the flank with 5×106 LS174T cells (human colorectal carcinoma) were either untreated controls (n=7) or bevacizumab treated (n=7). After 2 weeks, mice underwent F-FDG PET/CT. Calliper-measured tumor growth (Δvol) and final tumor volume (Volcal), F-FDG PET metabolically active volume (Volmet), mean metabolism (Metmean), and maximum metabolism (Metmax) were measured. Twenty-four texture features were compared between treated and untreated mice. Immunohistochemical mean tumor vascular density was estimated by anti-CD-34 staining after tumor resection. RESULTS: Treated mice had significantly lower tumor vascular density (P=0.032), confirming the antiangiogenic therapeutic effect of bevacizumab. None of the conventional measures were different between the two groups: Δvol (P=0.9), Volcal (P=0.7), Volmet (P=0.28), Metmax (P=0.7), or Metmean (P=0.32). One texture parameter, GLSZM-SZV (visually indicating that the F-FDG PET images of treated mice comprise uniformly sized clusters of different activity) had significantly different means between the two groups of mice (P=0.001). CONCLUSION: F-FDG PET derived texture parameters, particularly GLSZM-SZV, may be valid biomarkers of tumor response to treatment with bevacizumab, before change in volume.


Subject(s)
Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Fluorodeoxyglucose F18/metabolism , Positron Emission Tomography Computed Tomography , Tumor Burden , Animals , Bevacizumab/pharmacology , Biological Transport , Cell Transformation, Neoplastic , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Disease Models, Animal , Mice , Time Factors , Treatment Outcome
5.
Rehabil Oncol ; 35(3): 144-150, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28713659

ABSTRACT

BACKGROUND: Early mobilization protocols have been successfully implemented to improve function in critically ill patients; however, no study has focused on the oncology population. OBJECTIVES: To investigate the feasibility of early mobilization and describe the rehabilitation interventions and discharge outcomes in a cohort of critically ill patients with cancer. DESIGN: Retrospective review. METHODS: A retrospective analysis of patients with cancer who participated in occupational and physical therapy while on mechanical ventilation utilizing an institutional early mobilization protocol from June 2010 - July 2011, was completed. Demographic and clinical variables were abstracted, as well as occupational and physical therapy interventions. RESULTS: A cohort of 42 cancer patients on mechanical ventilation in the mixed medical/surgical intensive care unit of a comprehensive cancer center received early mobilization during the study period. The majority of participants demonstrated improved cognitive and functional status from the intensive care unit to hospital discharge. There were no reported adverse events during the occupational and physical therapy sessions. Among the 30 hospital survivors, 53% required continued rehabilitation services in their home environment and 40% were transferred to a rehabilitation facility. LIMITATIONS: Due to the small sample size, these findings are not generalizable to all critically ill cancer patients. There was no post-acute care follow-up of cognitive and physical functional performance. CONCLUSION: Early mobilization appears feasible in addressing the cognitive and functional needs of oncology patients in the intensive care unit.

6.
Transl Oncol ; 10(3): 459-467, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28456115

ABSTRACT

We evaluated magnetic resonance imaging (MRI) voxel heterogeneity following trastuzumab and/or cisplatin in a HER2+ esophageal xenograft (OE19) as a potential response biomarker. OE19 xenografts treated with saline (controls), monotherapy, or combined cisplatin and trastuzumab underwent 9.4-T MRI. Tumor MRI parametric maps of T1 relaxation time (pre/post contrast), T2 relaxation time, T2* relaxation rate (R2*), and apparent diffusion coefficient obtained before (TIME0), after 24hours (TIME1), and after 2weeks of treatment (TIME2) were analyzed. Voxel histogram and fractal parameters (from the whole tumor, rim and center, and as a ratio of rim-to-center) were derived. Tumors were stained for immunohistochemical markers of hypoxia (CA-IX), angiogenesis (CD34), and proliferation (Ki-67). Combination therapy reduced xenograft growth rate (relative change, ∆ +0.58±0.43 versus controls, ∆ +4.1±1.0; P=0.008). More spatially homogeneous voxel distribution between the rim to center was noted after treatment for combination therapy versus controls, respectively, for contrast-enhanced T1 relaxation time (90th percentile: ratio 1.00 versus 0.88, P=0.009), T2 relaxation time (mean: 1.00 versus 0.92, P=0.006; median: 0.98 versus 0.91, P=0.006; 75th percentile: 1.02 versus 0.94, P=0.007), and R2* (10th percentile: 0.99 versus 1.26, P=0.003). We found that combination and trastuzumab monotherapy reduced MRI spatial heterogeneity and growth rate compared to the control or cisplatin groups, the former providing adjunctive tumor response information.

7.
Nat Commun ; 6: 7920, 2015 Aug 10.
Article in English | MEDLINE | ID: mdl-26258640

ABSTRACT

Angiogenesis is essential for tissue development, wound healing and tissue perfusion, with its dysregulation linked to tumorigenesis, rheumatoid arthritis and heart disease. Here we show that pro-angiogenic stimuli couple to NADPH oxidase-dependent generation of oxidants that catalyse an activating intermolecular-disulphide between regulatory-RIα subunits of protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This is crucial to blood vessel growth as 'redox-dead' Cys17Ser RIα knock-in mice fully resistant to PKA disulphide-activation have deficient angiogenesis in models of hind limb ischaemia and tumour-implant growth. Disulphide-activation of PKA represents a new therapeutic target in diseases with aberrant angiogenesis.


Subject(s)
Gene Expression Regulation/physiology , Neovascularization, Physiologic/genetics , Animals , Aorta/physiology , Cattle , Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics , Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/metabolism , Endothelial Cells , Gene Knock-In Techniques , Hindlimb , Immunoprecipitation , Ischemia , Male , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/blood supply , Oxidation-Reduction , Signal Transduction , Vascular Endothelial Growth Factor A/pharmacology
8.
Semin Respir Crit Care Med ; 35(1): 112-28, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24481765

ABSTRACT

Lung cancer is the leading cause of cancer death in the United States. It is estimated that more than 228,000 new cases will be diagnosed in 2013, accounting for approximately 159,000 or 27% of all cancer deaths. Survival in these patients remains poor despite advances in surgery, definitive radiotherapy, and chemotherapy for primary and metastatic non-small cell lung cancer. Five-year relative survival rates remain at 27% for regional disease and 54% for node-negative disease. With the increasing personalization of therapy, there remains a need for better prognostic and predictive markers to direct patient management in lung cancer. Hypoxia and angiogenesis play an important role in the development and progression of lung cancer. Targeted and non-targeted imaging techniques in the preclinical and clinical setting, combined with advanced postprocessing techniques to assess tumor heterogeneity, may enable clinicians to better characterize lung tumors, and to predict and assess response to treatment. In this review, we summarize our current understanding of angiogenesis in lung cancer and discuss the available imaging techniques to assess this in the preclinical and clinical setting.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnosis , Lung Neoplasms/diagnosis , Neovascularization, Pathologic/diagnosis , Animals , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/blood supply , Carcinoma, Non-Small-Cell Lung/pathology , Diagnostic Imaging/methods , Disease Progression , Humans , Lung Neoplasms/blood supply , Lung Neoplasms/pathology , Neovascularization, Pathologic/pathology , Precision Medicine/methods , Prognosis , Survival Rate , United States
9.
Nucl Med Biol ; 40(1): 73-9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23062949

ABSTRACT

INTRODUCTION: The p53 tumour suppressor protein plays a pivotal role in the response of mammalian cells to DNA damage. It regulates cell cycle progression, apoptosis and DNA repair mechanisms and is therefore likely to influence response to targeted radionuclide therapy. This study investigated the role of p53 in the cellular response to the Auger-emitting radionuclide indium-111. METHODS: Two stable clones of a HT1080 fibrosarcoma cell line, differing only in p53 status due to RNAi-mediated knockdown of p53 expression, were incubated for 1 h with [¹¹¹In]-oxinate (0-10 MBq/ml). Radiopharmaceutical uptake into HT1080 cells was measured in situ using a non-contact phosphorimager method. Cellular sensitivity and DNA damage were measured by, respectively, clonogenic survival analysis and the single cell gel electrophoresis (Comet) assay. RESULTS: Mean uptake of [¹¹¹In]-oxinate in HT1080 cells was unaffected by p53 status, reaching a maximum of 9Bq/cell. [¹¹¹In]-oxinate-induced cytotoxicity was also identical in both clones, as measured by IC50 (0.68 MBq/ml). However the formation of DNA damage, measured immediately after treatment with [¹¹¹In]-oxinate, was found to be up to 2.5-fold higher in the p53-deficient HT1080 clone. CONCLUSIONS: The increased DNA damage induced in p53-deficient HT1080 cells suggests an early deficiency in the repair of DNA damage during the treatment period. However, the similarity in cellular sensitivity, irrespective of p53 status, suggests that reduced p53 leads to a concomitant reduction in p53-dependent cytotoxicity despite the persistence of DNA damage. The results may provide insight into how tumours that differ in p53 status respond to therapeutic radionuclides.


Subject(s)
Indium Radioisotopes/metabolism , Radiobiology , Radiopharmaceuticals/metabolism , Tumor Suppressor Protein p53/metabolism , Biological Transport , Cell Line, Tumor , Cell Survival/radiation effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA Damage , DNA Repair/radiation effects , Gene Expression Regulation, Neoplastic/radiation effects , Humans , Indium Radioisotopes/therapeutic use , Radiopharmaceuticals/therapeutic use
10.
Nucl Med Commun ; 32(2): 98-105, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21085047

ABSTRACT

PURPOSE: Accumulation of iodide and other substrates via the human sodium/iodide symporter (hNIS) is fundamental to imaging and therapy of thyroid disease, hNIS reporter gene imaging and hNIS-mediated gene therapy. There is no readily available positron emission tomography (PET) tracer for hNIS. Our aim was to develop a colon carcinoma cell line stably expressing hNIS, and use it to evaluate a novel hNIS PET tracer, [18F]-tetrafluoroborate. METHODS: Colon carcinoma cell line, HCT116, was stably transfected with hNIS, thus producing a cell line, HCT116-C19, with high hNIS expression. A Fisher rat thyroid cell line, FRTL5, which expresses rat sodium/iodide symporter when stimulated with thyroid-stimulating hormone, was used for comparison. Accumulation of [188Re]-perrhenate, [99mTc]-pertechnetate and [18F]-tetrafluoroborate was evaluated with and without perchlorate inhibition using an automated radioimmune assay system, LigandTracer. The affinity of [18F]-tetrafluoroborate for hNIS, and its half-maximal inhibitory concentration (IC50) for the inhibition of [99mTc]-pertechnetate transport were determined from the plateau accumulation of [18F]-tetrafluoroborate and [99mTc]-pertechnetate, respectively, as a function of tetrafluoroborate concentration. RESULTS: [18F]-tetrafluoroborate accumulated effectively in both FRTL5 and HCT116-C19 cells. The accumulation in HCT116-C19 cells (plateau accumulation 31%) was comparable to that of [188Re]-perrhenate (41%) and [99mTc]-pertechnetate (46%). Its affinity for hNIS and half-maximal inhibitory concentration (IC50) for the inhibition of pertechnetate uptake was approximately micromolar. CONCLUSION: We have produced a human colon cell line with a stable constitutive expression of functional hNIS (HCT116-hNIS-C19). [18F]-tetrafluoroborate accumulates in cells expressing hNIS or rat sodium/iodide symporter and is a potential PET imaging agent in thyroid disease and hNIS reporter gene imaging.


Subject(s)
Boric Acids , Colonic Neoplasms/pathology , Fluorine Radioisotopes , Gene Expression Regulation, Neoplastic , Positron-Emission Tomography/methods , Symporters/genetics , Animals , Biological Transport/drug effects , Borates , Boric Acids/metabolism , Borohydrides/pharmacology , Cloning, Molecular , Colonic Neoplasms/diagnostic imaging , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , DNA, Complementary/genetics , HCT116 Cells , Humans , Kinetics , Radioactivity , Rats , Rhenium/metabolism , Sodium Pertechnetate Tc 99m/metabolism , Transfection
11.
Eur J Nucl Med Mol Imaging ; 37(11): 2108-16, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20577737

ABSTRACT

PURPOSE: The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters (123)I-iodide, (131)I-iodide and (99m)Tc-pertechnetate. However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate (18)F-labelled tetrafluoroborate ([(18)F]TFB) for PET imaging of hNIS. METHODS: [(18)F]TFB was prepared by isotopic exchange of BF (4) (-) with [(18)F]fluoride in hot hydrochloric acid and purified using an alumina column. Its identity, purity and stability in serum were determined by HPLC, thin-layer chromatography (TLC) and mass spectrometry. Its interaction with NIS was assessed in vitro using FRTL-5 rat thyroid cells, with and without stimulation by thyroid-stimulating hormone (TSH), in the presence and absence of perchlorate. Biodistribution and PET imaging studies were performed using BALB/c mice, with and without perchlorate inhibition. RESULTS: [(18)F]TFB was readily prepared with specific activity of 10 GBq/mg. It showed rapid accumulation in FRTL-5 cells that was stimulated by TSH and inhibited by perchlorate, and rapid specific accumulation in vivo in thyroid (SUV = 72 after 1 h) and stomach that was inhibited 95% by perchlorate. CONCLUSION: [(18)F]TFB is an easily prepared PET imaging agent for rodent NIS and should be evaluated for hNIS PET imaging in humans.


Subject(s)
Boric Acids/chemical synthesis , Genes, Reporter , Molecular Imaging/methods , Positron-Emission Tomography/methods , Symporters/genetics , Thyroid Diseases/diagnostic imaging , Animals , Borates , Boric Acids/metabolism , Boric Acids/pharmacokinetics , Cell Line , Drug Stability , Female , Fluorine Radioisotopes , Humans , Male , Mice , Rats , Symporters/metabolism , Thyroid Diseases/metabolism , Thyroid Gland/cytology , Thyroid Gland/metabolism
12.
Eur J Nucl Med Mol Imaging ; 37(2): 330-8, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19915836

ABSTRACT

PURPOSE: Hypoxia occurs frequently in cancers and can lead to therapeutic resistance due to poor perfusion and loss of the oxygen enhancement effect. (64)Cu-ATSM has shown promise as a hypoxia diagnostic agent due to its selective uptake and retention in hypoxic cells and its emission of positrons for PET imaging. (64)Cu also emits radiotoxic Auger electrons and beta(-) particles and may therefore exhibit therapeutic potential when concentrated in hypoxic tissue. METHODS: MCF-7 cells were treated with 0-10 MBq/ml (64)Cu-ATSM under differing oxygen conditions ranging from normoxia to severe hypoxia. Intracellular response to hypoxia was measured using Western blotting for expression of HIF-1alpha, while cellular accumulation of (64)Cu was measured by gamma counting. DNA damage and cytotoxicity were measured with, respectively, the Comet assay and clonogenic survival. RESULTS: (64)Cu-ATSM uptake in MCF-7 cells increased as atmospheric oxygen decreased (up to 5.6 Bq/cell at 20.9% oxygen, 10.4 Bq/cell at 0.1% oxygen and 26.0 Bq/cell at anoxia). Toxicity of (64)Cu-ATSM in MCF-7 cells also increased as atmospheric oxygen decreased, with survival of 9.8, 1.5 and 0% in cells exposed to 10 MBq/ml at 20.9, 0.1 and 0% oxygen. The Comet assay revealed a statistically significant increase in (64)Cu-ATSM-induced DNA damage under hypoxic conditions. CONCLUSION: The results support a model in which hypoxia-enhanced uptake of radiotoxic (64)Cu induces sufficient DNA damage and toxicity to overcome the documented radioresistance in hypoxic MCF-7 cells. This suggests that (64)Cu-ATSM and related complexes have potential for targeted radionuclide therapy of hypoxic tumours.


Subject(s)
DNA Damage , Organometallic Compounds/metabolism , Organometallic Compounds/pharmacology , Radiobiology , Thiosemicarbazones/metabolism , Thiosemicarbazones/pharmacology , Biological Transport , Cell Hypoxia , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Coordination Complexes , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Oxygen/metabolism
13.
Br J Clin Pharmacol ; 66(2): 261-5, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18507658

ABSTRACT

AIMS: Repeated adenosine monophosphate (AMP) challenges are used to assess drug efficacy in clinical trials of mild, steroid-naive asthmatics. Refractoriness has been reported after repeated challenges over short intervals. This study evaluated possible tachyphylaxis after repeated AMP challenges at 12 and 24 h in mild, steroid-naive asthmatics. METHODS: This was an open, three-way crossover study. Twenty-six steroid-naive asthmatic subjects were randomized to the following AMP challenge regimens separated by 7-14 days: (A) challenge at 08.00 h, repeated 24 h later; (B) challenge at 08.00 h, repeated 12 and 24 h later; (C) challenge at 20.00 h, repeated 12 h later. Comparisons within day were assessed using 90% confidence intervals (CIs). Non-inferiority approach taken with 1 doubling concentration (DC) as a clinically relevant difference. RESULTS: Regimen A: Significant increase in AMP reactivity at 24 h. Mean DC difference was 0.6 (90% CI 0.24, 0.96). Regimen B: No evidence of difference between AMP reactivity at 08.00 h and a repeated challenge 12 h later. Repeated challenge at 24 h caused a significant increase in provocation concentration (PC)(20) compared with 12 h (mean DC difference 0.48, 90% CI 0.02, 0.95) and 0 h (mean DC difference 0.82, 90% CI 0.49, 1.14 - the upper CI exceeds the criteria of 1 DC). Challenge regimen C: No difference between challenges; mean DC difference of 0.28 (90% CI -0.2, 0.76). CONCLUSION: The small decline in AMP reactivity during repeated challenges was not consistently observed, and was small compared with the known effects of inhaled drugs.


Subject(s)
Adenosine Monophosphate , Asthma/diagnosis , Bronchial Hyperreactivity/prevention & control , Tachyphylaxis/physiology , Administration, Inhalation , Adult , Asthma/physiopathology , Bronchial Provocation Tests/methods , Cross-Over Studies , Female , Forced Expiratory Volume/physiology , Humans , Male , Reproducibility of Results , Therapeutics
14.
Eval Rev ; 31(2): 153-65, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17356181

ABSTRACT

Cross-cultural adaptation of study instruments is a difficult, time-consuming, but arguably cost-effective process. If conducted properly, it has the advantage that the translated study instruments are accurate, easy to understand, accessible, and culturally appropriate to the target audience and produce reliable and valid data. This article explores issues, challenges, and solutions for translating a set of research instruments used in a randomized, controlled trial for four separate community languages (Chinese, Vietnamese, Greek, Italian).


Subject(s)
Cross-Cultural Comparison , Language , Program Development/methods , Translating , Humans , Randomized Controlled Trials as Topic
15.
Curr Opin Chem Biol ; 10(5): 465-72, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16931112

ABSTRACT

A fascinating group of enzymes has been shown to possess multiple active sites connected by intramolecular tunnels for the passage of reactive intermediates from the site of production to the site of utilization. In most of the examples studied to date, the binding of substrates at one active site enhances the formation of a reaction intermediate at an adjacent active site. The most common intermediate is ammonia, derived from the hydrolysis of glutamine, but molecular tunnels for the passage of indole, carbon monoxide, acetaldehyde and carbamate have also been identified. The architectural features of these molecular tunnels are quite different from one another, suggesting that they evolved independently.


Subject(s)
Enzymes/chemistry , Binding Sites , Catalysis , Enzymes/metabolism , Ligands , Molecular Structure , Protein Conformation , Protein Structure, Secondary
16.
Patient Educ Couns ; 64(1-3): 360-8, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16859871

ABSTRACT

OBJECTIVE: This study investigated the effectiveness of the Chronic Disease Self-management Program (CDSMP) when delivered to for people from Vietnamese, Chinese, Italian and Greek backgrounds living in Victoria, Australia. METHOD: The CDSMP was administered to 320 people with chronic illnesse(es) in selected low income areas in the State of Victoria, Australia. At 6 months, they were compared with randomised wait-list control subjects (n=154) using analyses of covariance. RESULTS: Participants in the intervention group had significantly better outcomes on energy, exercise, symptom management, self-efficacy, general health, pain, fatigue and health distress. There were no significant effects for health services utilisation. Interactions across language groups were observed with the Vietnamese and Chinese speaking participants gaining greater benefit. CONCLUSION: Self-management programs can be successfully implemented with culturally and linguistically diverse populations in Australia. Further research is needed to evaluate long-term outcomes; explore effects on service utilisation; and to determine whether the benefits obtained from participating in a self-management program can be maintained. PRACTICE IMPLICATIONS: Self-management programs should be considered for people from culturally and linguistically diverse backgrounds. Care also needs to be taken in designing recruitment strategies to minimize withdrawal rates and to ensure harder to reach people are given encouragement to participate.


Subject(s)
Chronic Disease , Cultural Diversity , Disease Management , Patient Education as Topic/organization & administration , Self Care , Aged , Analysis of Variance , China/ethnology , Chronic Disease/ethnology , Chronic Disease/prevention & control , Female , Follow-Up Studies , Greece/ethnology , Health Knowledge, Attitudes, Practice , Health Status , Humans , Italy/ethnology , Male , Outcome Assessment, Health Care , Patient Satisfaction/ethnology , Poverty Areas , Program Evaluation , Self Care/methods , Self Care/psychology , Self Efficacy , Surveys and Questionnaires , Victoria , Vietnam/ethnology
17.
Biochemistry ; 45(7): 1997-2005, 2006 Feb 21.
Article in English | MEDLINE | ID: mdl-16475788

ABSTRACT

The functional assignment of enzymes that catalyze unknown chemical transformations is a difficult problem. The protein Pa5106 from Pseudomonas aeruginosa has been identified as a member of the amidohydrolase superfamily by a comprehensive amino acid sequence comparison with structurally authenticated members of this superfamily. The function of Pa5106 has been annotated as a probablechlorohydrolase or cytosine deaminase. A close examination of the genomic content of P. aeruginosa reveals that the gene for this protein is in close proximity to genes included in the histidine degradation pathway. The first three steps for the degradation of histidine include the action of HutH, HutU, and HutI to convert L-histidine to N-formimino-L-glutamate. The degradation of N-formimino-L-glutamate to L-glutamate can occur by three different pathways. Three proteins in P. aeruginosa have been identified that catalyze two of the three possible pathways for the degradation of N-formimino-L-glutamate. The protein Pa5106 was shown to catalyze the deimination of N-formimino-L-glutamate to ammonia and N-formyl-L-glutamate, while Pa5091 catalyzed the hydrolysis of N-formyl-L-glutamate to formate and L-glutamate. The protein Pa3175 is dislocated from the hut operon and was shown to catalyze the hydrolysis of N-formimino-L-glutamate to formamide and L-glutamate. The reason for the coexistence of two alternative pathways for the degradation of N-formimino-L-glutamate in P. aeruginosa is unknown.


Subject(s)
Amidohydrolases/metabolism , Hydrolases/metabolism , Amino Acid Sequence , Glutamates/pharmacology , Hydrolases/antagonists & inhibitors , Hydrolases/genetics , Kinetics , Molecular Sequence Data , Mutagenesis, Site-Directed , Pseudomonas aeruginosa/enzymology , Sequence Alignment , Substrate Specificity
18.
Health Expect ; 8(4): 315-23, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16266419

ABSTRACT

BACKGROUND: Chronic disease self-management programmes are now an important adjunct to the treatment and care of Australians with chronic illnesses. Most programmes are delivered in English and cater for 'Anglo' views of health and illness. The Peer-Led Self-Management of Chronic Illness Project was funded by the National Health and Medical Research Council (NHMRC) to test the hypothesis that the Stanford University Chronic Disease Self-Management Program would improve health outcomes for people from the Vietnamese, Greek, Chinese and Italian communities in Melbourne's north-eastern suburbs. OBJECTIVE: To examine the extent to which the programme required modification so that the concepts associated with self-management programmes have relevance to the health behaviours of people with chronic illness from the above communities. METHODS: Four focus groups facilitated in English, using interpreters. RESULTS: There was wide understanding of the concepts employed in self-management programmes. Literacy problems emerged as the major obstacle to participating in unmodified programmes. CONCLUSION: The conceptual aspects of the programme require less modification than originally predicted, but the programme requires sensitive modification so that it is accessible to people with low literacy levels.


Subject(s)
Ethnicity , Health Behavior , Self Care , Aged , Aged, 80 and over , Chronic Disease , Cultural Diversity , Female , Focus Groups , Humans , Male , Middle Aged , Victoria
19.
Bioorg Med Chem ; 12(7): 1737-49, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-15028265

ABSTRACT

Structure-guided design was employed in a search for potent and selective inhibitors of mammalian secreted phospholipases A(2) (sPLA(2)s). Using the X-ray structures of human groups IIA and X sPLA(2)s (hGIIA and hGX) as templates, homology structural models were made for the other human and mouse sPLA(2)s (hGIB, mGIB, mGIIA, mGIIC, hGIID, mGIID, hGIIE, mGIIE, hGIIF, mGIIF, hGV, mGV, and mGX). Me-Indoxam is a previously discovered indole analogue that binds tightly to many sPLA(2)s, and the X-ray structure of the hGX-Me-Indoxam complex was determined at a resolution of 2.0 A. Modeling suggests that the residues near the N(1)-substituent of Me-Indoxam vary significantly among the mammalian sPLA(2)s, and therefore a library of 83N(1)-variants was prepared by parallel synthesis. Several Me-Indoxam analogues bearing a 4-(2-oxy-ethanoic acid) side chain were potent inhibitors (IC(50) <0.05 microM) of hGIIA, mGIIA, mGIIC, hGIIE, mGIIE, hGV, and mGV, while they displayed intermediate potency (0.05-5 microM) against hGIB, mGIB, hGX, and mGX, and poorly inhibited (>5 microM) hGIID, mGIID, hGIIF, and mGIIF. Me-Indoxam analogues bearing a 5-(4-oxy-butanoic acid) side chain were generally less potent inhibitors. Although no compounds were found to be highly specific for a single human or mouse sPLA(2), combinations of Me-Indoxam analogues were discovered that could be used to distinguish the action of various sPLA(2)s in cellular events. For example, Me-Indoxam and compound 5 are approximately 5-fold more potent on hGIIA than on hGV, and compound 21 is 10-fold more potent on hGV versus hGIIA.


Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Indoles/pharmacology , Phospholipases A/antagonists & inhibitors , Phospholipases A/chemistry , Animals , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Group II Phospholipases A2 , Group X Phospholipases A2 , Humans , Indoles/chemical synthesis , Indolizines/chemistry , Indolizines/pharmacology , Mice , Molecular Structure , Structure-Activity Relationship
20.
Cerebrovasc Dis ; 17(2-3): 111-7, 2004.
Article in English | MEDLINE | ID: mdl-14707409

ABSTRACT

While planning the GAIN International Study of gavestinel in acute stroke, a sequential triangular test was proposed but not implemented. Before the trial commenced it was agreed to evaluate the sequential design retrospectively to evaluate the differences in the resulting analyses, trial durations and sample sizes in order to assess the potential of sequential procedures for future stroke trials. This paper presents four sequential reconstructions of the GAIN study made under various scenarios. For the data as observed, the sequential design would have reduced the trial sample size by 234 patients and shortened its duration by 3 or 4 months. Had the study not achieved a recruitment rate that far exceeded expectation, the advantages of the sequential design would have been much greater. Sequential designs appear to be an attractive option for trials in stroke.


Subject(s)
Clinical Trials, Phase III as Topic/methods , Excitatory Amino Acid Antagonists/therapeutic use , Indoles/therapeutic use , Randomized Controlled Trials as Topic/methods , Stroke/drug therapy , Acute Disease , Humans , Neuroprotective Agents/therapeutic use , Patient Selection , Retrospective Studies , Treatment Outcome
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