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Sökning: WFRF:(Tran Thuy)

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1.
  • Tran, Ngoc Hieu, et al. (författare)
  • Genetic profiling of Vietnamese population from large-scale genomic analysis of non-invasive prenatal testing data
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The under-representation of several ethnic groups in existing genetic databases and studies have undermined our understanding of the genetic variations and associated traits or diseases in many populations. Cost and technology limitations remain the challenges in performing large-scale genome sequencing projects in many developing countries, including Vietnam. As one of the most rapidly adopted genetic tests, non-invasive prenatal testing (NIPT) data offers an alternative untapped resource for genetic studies. Here we performed a large-scale genomic analysis of 2683 pregnant Vietnamese women using their NIPT data and identified a comprehensive set of 8,054,515 single-nucleotide polymorphisms, among which 8.2% were new to the Vietnamese population. Our study also revealed 24,487 disease-associated genetic variants and their allele frequency distribution, especially 5 pathogenic variants for prevalent genetic disorders in Vietnam. We also observed major discrepancies in the allele frequency distribution of disease-associated genetic variants between the Vietnamese and other populations, thus highlighting a need for genome-wide association studies dedicated to the Vietnamese population. The resulted database of Vietnamese genetic variants, their allele frequency distribution, and their associated diseases presents a valuable resource for future genetic studies.
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2.
  • Lam, Thua-Phong, et al. (författare)
  • Flavonoids as dual-target inhibitors against α-glucosidase and α-amylase : a systematic review of in vitro studies
  • 2024
  • Ingår i: NATURAL PRODUCTS AND BIOPROSPECTING. - : Springer. - 2192-2195 .- 2192-2209. ; 14:1
  • Forskningsöversikt (refereegranskat)abstract
    • Diabetes mellitus remains a major global health issue, and great attention is directed at natural therapeutics. This systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating their inhibitory effects on alpha-glucosidase and alpha-amylase, two key enzymes involved in starch digestion. Six scientific databases (PubMed, Virtual Health Library, EMBASE, SCOPUS, Web of Science, and WHO Global Index Medicus) were searched until August 21, 2022, for in vitro studies reporting IC50 values of purified flavonoids on alpha-amylase and alpha-glucosidase, along with corresponding data for acarbose as a positive control. A total of 339 eligible articles were analyzed, resulting in the retrieval of 1643 flavonoid structures. These structures were rigorously standardized and curated, yielding 974 unique compounds, among which 177 flavonoids exhibited inhibition of both alpha-glucosidase and alpha-amylase are presented. Quality assessment utilizing a modified CONSORT checklist and structure-activity relationship (SAR) analysis were performed, revealing crucial features for the simultaneous inhibition of flavonoids against both enzymes. Moreover, the review also addressed several limitations in the current research landscape and proposed potential solutions. The curated datasets are available online at https://github.com/MedChemUMP/FDIGA.
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3.
  • Pham, Binh Thai, et al. (författare)
  • Performance Evaluation of Machine Learning Methods for Forest Fire Modeling and Prediction
  • 2020
  • Ingår i: Symmetry. - Switzerland : MDPI. - 2073-8994. ; 12:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Predicting and mapping fire susceptibility is a top research priority in fire-prone forests worldwide. This study evaluates the abilities of the Bayes Network (BN), Naïve Bayes (NB), Decision Tree (DT), and Multivariate Logistic Regression (MLP) machine learning methods for the prediction and mapping fire susceptibility across the Pu Mat National Park, Nghe An Province, Vietnam. The modeling methodology was formulated based on processing the information from the 57 historical fires and a set of nine spatially explicit explanatory variables, namely elevation, slope degree, aspect, average annual temperate, drought index, river density, land cover, and distance from roads and residential areas. Using the area under the receiver operating characteristic curve (AUC) and seven other performance metrics, the models were validated in terms of their abilities to elucidate the general fire behaviors in the Pu Mat National Park and to predict future fires. Despite a few differences between the AUC values, the BN model with an AUC value of 0.96 was dominant over the other models in predicting future fires. The second best was the DT model (AUC = 0.94), followed by the NB (AUC = 0.939), and MLR (AUC = 0.937) models. Our robust analysis demonstrated that these models are sufficiently robust in response to the training and validation datasets change. Further, the results revealed that moderate to high levels of fire susceptibilities are associated with ~19% of the Pu Mat National Park where human activities are numerous. This study and the resultant susceptibility maps provide a basis for developing more efficient fire-fighting strategies and reorganizing policies in favor of sustainable management of forest resources.
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4.
  • Eriksson, Leif, 1971-, et al. (författare)
  • Secular trend, seasonality and effects of a community-based intervention on neonatal mortality : follow-up of a cluster-randomised trial in Quang Ninh province, Vietnam
  • 2018
  • Ingår i: Journal of Epidemiology and Community Health. - : BMJ. - 0143-005X .- 1470-2738. ; 72:9, s. 776-782
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Little is know about whether the effects of community engagement interventions for child survival in low-income and middle-income settings are sustained. Seasonal variation and secular trend may blur the data. Neonatal mortality was reduced in a cluster-randomised trial in Vietnam where laywomen facilitated groups composed of local stakeholders employing a problem-solving approach for 3 years. In this analysis, we aim at disentangling the secular trend, the seasonal variation and the effect of the intervention on neonatal mortality during and after the trial.Methods: In Quang Ninh province, 44 communes were allocated to intervention and 46 to control. Births and neonatal deaths were assessed in a baseline survey in 2005, monitored during the trial in 2008–2011 and followed up by a survey in 2014. Time series analyses were performed on monthly neonatal mortality data.Results: There were 30 187 live births and 480 neonatal deaths. The intervention reduced the neonatal mortality from 19.1 to 11.6 per 1000 live births. The reduction was sustained 3 years after the trial. The control areas reached a similar level at the time of follow-up. Time series decomposition analysis revealed a downward trend in the intervention areas during the trial that was not found in the control areas. Neonatal mortality peaked in the hot and wet summers.Conclusions: A community engagement intervention resulted in a lower neonatal mortality rate that was sustained but not further reduced after the end of the trial. When decomposing time series of neonatal mortality, a clear downward trend was demonstrated in intervention but not in control areas.Trial registration number: ISRCTN44599712, Post-results.
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5.
  • Ha, Do Thi, et al. (författare)
  • Anti-inflammatory effect of oligostilbenoids from Vitis heyneana in LPS-stimulated RAW 264.7 macrophages via suppressing the NF-ΚB activation
  • 2018
  • Ingår i: Chemistry Central Journal. - : Springer Science and Business Media LLC. - 1752-153X. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Vitis heyneana is widely distributed in the north of Vietnam, it has been used in Vietnamese traditional medicine as an agent for treatment of arthritis, bronchitis, carbuncles and inflammatory conditions, and menstrual irregularities. However, this plant has not been investigated in phytochemical constituents and biological effects, especially in the anti-inflammatory property. Results: Bioassay-guided fractionation of the EtOAc soluble fraction from the aerial part of Vitis heyneana resulted in the isolation of a series of oligostilbenoids as piceid (1), 2-r-viniferin (2), betulifol A (3), vitisinol C (4), (-)-trans-ε-viniferin (5), α-viniferin (6), shoreaketon (7), amurensin B (8), vitisinol B (9), and cis-vitisin B (10). Compound 5 showed the most potent inhibitory activities by suppressing LPS-induced COX-2 expression and PGE2 production. This compound exhibited significantly reduced LPS-induced nitric oxide (NO) release in a dose-dependent manner. These effects are accompanied with the inhibition of transcription factor NF-ΚB activation. Conclusion: The results suggested that trans-ε-viniferin exerts anti-inflammatory effects via suppression the NF-ΚB activation in RAW 264.7 cells. [Figure not available: see fulltext.]
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6.
  • Nguyen-Tien, Thang, et al. (författare)
  • The Distribution and Composition of Vector Abundance in Hanoi City, Vietnam : Association with Livestock Keeping and Flavivirus Detection
  • 2021
  • Ingår i: Viruses. - : MDPI. - 1999-4915. ; 13:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Dengue virus and Japanese encephalitis virus are two common flaviviruses that are spread widely by Aedes and Culex mosquitoes. Livestock keeping is vital for cities; however, it can pose the risk of increasing the mosquito population. Our study explored how livestock keeping in and around a large city is associated with the presence of mosquitoes and the risk of them spreading flaviviruses.Methods: An entomological study was conducted in 6 districts with 233 households with livestock, and 280 households without livestock, in Hanoi city. BG-Sentinel traps and CDC light traps were used to collect mosquitoes close to animal farms and human habitats. Adult mosquitoes were counted, identified to species level, and grouped into 385 pools, which were screened for flaviviruses using a pan-flavivirus qPCR protocol and sequencing.Results: A total of 12,861 adult mosquitoes were collected at the 513 households, with 5 different genera collected, of which the Culex genus was the most abundant. Our study found that there was a positive association between livestock keeping and the size of the mosquito population-most predominantly between pig rearing and Culex species (p < 0.001). One pool of Cx. tritaeniorhynchus, collected in a peri-urban district, was found to be positive for Japanese encephalitis virus.Conclusions: The risk of flavivirus transmission in urban areas of Hanoi city due to the spread of Culex and Aedes mosquitoes could be facilitated by livestock keeping.
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7.
  • Persson, Lars-Åke, 1947-, et al. (författare)
  • Effect of facilitation of local maternal-and-newborn stakeholder groups on neonatal mortality : cluster-randomized controlled trial
  • 2013
  • Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam.METHODS AND FINDINGS: In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73-1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30-0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07-4.8]).CONCLUSIONS: A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.TRIAL REGISTRATION: Current Controlled Trials ISRCTN44599712. Please see later in the article for the Editors' Summary.
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8.
  • Phan, Hang Thi, et al. (författare)
  • An educational intervention to improve hand hygiene compliance in Vietnam
  • 2018
  • Ingår i: BMC Infectious Diseases. - : BIOMED CENTRAL LTD. - 1471-2334. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Hand hygiene compliance is the basis of infection control programs. In developing countries models to improve hand hygiene compliance to reduce healthcare acquired infections are required. The aim of this study was to determine hand hygiene compliance following an educational program in an obstetric and gynecological hospital in Vietnam.Methods: Health care workers from neonatal intensive care, delivery suite and a surgical ward from Hung Vuong Hospital, Ho Chi Minh City, Vietnam undertook a 4-h educational program targeting hand hygiene. Compliance was monitored monthly for six months following the intervention. Hand hygiene knowledge was assessed at baseline and after six months of the study.Results: There were 7124 opportunities over 370 hand hygiene recording sessions with 1531 opportunities at baseline and 1620 at 6 months following the intervention. Hand hygiene compliance increased significantly from baseline across all sites (43.6% [95% Confidence interval CI:41.1-46.1] to 63% [95% CI:60.6-65.3]; p < 0.0001). Health care worker hand hygiene compliance increased significantly after intervention (p < 0.0001). There were significant improvements in knowledge scores from baseline to 2 months post educational intervention with mean difference standard deviations (SD):1.5 (2.5); p < 0.001).Conclusions: A simple educational model was implemented in a Vietnamese hospital that revealed good hand hygiene compliance for an extended period of time. Hand hygiene knowledge increased during the intervention. This hand hygiene model could be used in developing countries were resources are limited.
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9.
  • Tran, Thi-Thuy-Quynh, et al. (författare)
  • Network Coding with Multimedia Transmission and Cognitive Networking: An Implementation based on Software-Defined Radio
  • 2020
  • Ingår i: REV Journal on Electronics and Communications. ; 10:3-4, s. 72-84
  • Tidskriftsartikel (refereegranskat)abstract
    • Network coding (NC) is considered a breakthrough to improve throughput, robustness, and security of wireless networks. Although the theoretical aspects of NC have been extensively investigated, there have been only few experiments with pure NC schematics. This paper presents an implementation of NC under a two-way relay model and extends it to two non-straightforward scenarios: (i) multimedia transmission with layered coding and multiple-description coding, and (ii) cognitive radio with Vandermonde frequency division multiplexing (VFDM). The implementation is in real time and based on software-defined radio (SDR). The experimental results show that, by combining NC and source coding, we can control the quality of the received multimedia content in an on-demand manner. Whereas in the VFDM-based cognitive radio, the quality of the received content in the primary receiver is low (due to imperfect channel estimation) yet retrievable. Our implementation results serve as a proof for the practicability of network coding in relevant applications.
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10.
  • Trinh, Duc Anh, et al. (författare)
  • Impact of terrestrial runoff on organic matter, trophic state, and phytoplankton in a tropical, upland reservoir
  • 2016
  • Ingår i: Aquatic Sciences. - : Springer Science and Business Media LLC. - 1015-1621 .- 1420-9055. ; 78:2, s. 367-379
  • Tidskriftsartikel (refereegranskat)abstract
    • The impact of organic matter inputs from agricultural, forest and domestic sources on aquatic processes has been considerably less studied in tropical reservoirs relative to temperate systems despite the high number of these small aquatic systems in the tropics. Here we present the results of an in situ mesocosm study that examined the impact of allochthonous organic matter on a headwater reservoir in Northern Vietnam. We examined the impact of wastewater and soils from floodplain paddies, Acacia mangium plantations and from upland slopes on the metabolic status of the reservoir. The addition of floodplain paddy soils to the reservoir water led to a rapid switch in metabolic status from net autotrophic to net heterotrophic. In contrast, the addition of wastewater in low concentrations had less impact on the metabolic status of the reservoir, reflecting the low population density in the area. The addition of floodplain paddy soils also increased phytoplankton diversity and evenness relative to the control. In summary, soils from floodplain paddies and from A. mangium plantations had the highest impact on the reservoir, with upland soils and wastewater having less of an impact. We also found that primary production in this reservoir was nitrogen limited. In order to avoid accelerating the impact of runoff on the reservoir, future management options should perhaps focus on minimizing water and sediment runoff from upstream paddy fields and from A. mangium plantations. These results also underline the importance of studying these upland tropical water bodies that can contribute an important but, on the whole, ignored part of the global carbon balance.
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11.
  • Ahlgren, Sara, et al. (författare)
  • Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
  • 2009
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 50:5, s. 781-789
  • Tidskriftsartikel (refereegranskat)abstract
    • The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.
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12.
  • Ahlstedt, Jonas, et al. (författare)
  • Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.
  • 2015
  • Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 5:4, s. 333-347
  • Tidskriftsartikel (refereegranskat)abstract
    • Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.
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13.
  • Ahlstedt, Jonas, et al. (författare)
  • Human Anti-Oxidation Protein A1M-A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.
  • 2015
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 16:12, s. 30309-30320
  • Forskningsöversikt (refereegranskat)abstract
    • Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.
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14.
  • Altena, Renske, et al. (författare)
  • Current status of contemporary diagnostic radiotracers in the management of breast cancer : first steps toward theranostic applications
  • 2023
  • Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 13:1
  • Forskningsöversikt (refereegranskat)abstract
    • BackgroundExpanding therapeutic possibilities have improved disease-related prospects for breast cancer patients. Pathological analysis on a tumor biopsy is the current reference standard biomarker used to select for treatment with targeted anticancer drugs. This method has, however, several limitations, related to intra- and intertumoral as well as spatial heterogeneity in receptor expression as well as the need to perform invasive procedures that are not always technically feasible.Main bodyIn this narrative review, we focus on the current role of molecular imaging with contemporary radiotracers for positron emission tomography (PET) in breast cancer. We provide an overview of diagnostic radiotracers that represent treatment targets, such as programmed death ligand 1, human epidermal growth factor receptor 2, polyadenosine diphosphate-ribose polymerase and estrogen receptor, and discuss developments in therapeutic radionuclides for breast cancer management.ConclusionImaging of treatment targets with PET tracers may provide a more reliable precision medicine tool to find the right treatment for the right patient at the right time. In addition to visualization of the target of treatment, theranostic trials with alpha- or beta-emitting isotopes provide a future treatment option for patients with metastatic breast cancer.
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15.
  • Dahal, Prabin, et al. (författare)
  • Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
  • 2019
  • Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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16.
  • Dahal, Prabin, et al. (författare)
  • Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy : an individual participant data meta-analysis
  • 2022
  • Ingår i: Malaria Journal. - : Springer Nature. - 1475-2875. ; 21
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria.Methods: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up.Results: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with <= 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution.Conclusions: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
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17.
  • Dahlbom, Magnus, et al. (författare)
  • Effects of high photon fluence rate from therapeutic radionuclides on preclinical and clinical PET systems
  • 2016
  • Ingår i: 2014 IEEE Nuclear Science Symposium and Medical Imaging Conference, NSS/MIC 2014. - 9781479960972
  • Konferensbidrag (refereegranskat)abstract
    • Tumor response in radionuclide therapy can be monitored with PET/CT and/or PET/MR. A high background photon fluence from a therapy radionuclide may influence both image quality and quantification, when imaging is performed intra-therapeutically, i.e. with high activity of the therapeutic radionuclide present. Here, count losses and image distortion have been investigated for preclinical and clinical PET systems with different detector designs. The effect on the spatial resolution was studied with a point source of 22Na in a background of 99mTc, where 99mTc emulated the photon emission from a therapeutic radionuclide. An in-house made mouse phantom with silicon tubes filled with 99mTc with a centrally placed 22Na point source was used. For the clinical systems, a 70 cm long NEMA PET Scatter Phantom was used, with a 22Na point source placed at the center whereas the off-center silicon tube was filled with 99mTc. In addition, image quality was also evaluated in the presence of different levels of 99mTc with a 18F-filled NEMA image quality phantom on the preclinical systems and a 18F-filled Jaszczak phantom on the clinical system. Preclinical PET systems with different detector geometries showed that the addition of 99mTc affected the count rate capability considerably, especially those with a low number of read-out channels. The coincidence rate for was significantly reduced when high activities of 99mTc were present. The clinical PET system also showed an effect of reduced coincidence rate with increased photon fluence rate. At high 99mTc activities, the spatial resolution was degraded for both the preclinical and the clinical systems. The quantitative capability of PET systems used intra-therapeutically is significantly affected by the additional high photon fluence rate. The dead-time correction implemented on some of the investigated PET systems, was able to accurately compensate for the coincidence count losses. The reduced spatial resolution at high photon fluence rate, however, remains a potentially limiting factor.
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18.
  • Ekblad, Torun, et al. (författare)
  • Development and preclinical characterisation of 99mTc-labelled Affibody molecules with reduced renal uptake
  • 2008
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 35:12, s. 2245-2255
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose  Affibody molecules are low molecular weight proteins (7 kDa), which can be selected to bind to tumour-associated target proteins with subnanomolar affinity. Because of rapid tumour localisation and clearance from nonspecific compartments, Affibody molecules are promising tracers for molecular imaging. Earlier, 99mTc-labelled Affibody molecules demonstrated specific targeting of tumour xenografts. However, the biodistribution was suboptimal either because of hepatobiliary excretion or high renal uptake of the radioactivity. The goal of this study was to optimise the biodistribution of Affibody molecules by chelator engineering. Materials and methods  Anti-HER2 ZHER2:342 Affibody molecules, carrying the mercaptoacetyl-glutamyl-seryl-glutamyl (maESE), mercaptoacetyl-glutamyl-glutamyl-seryl (maEES) and mercaptoacetyl-seryl-glutamyl-glutamyl (maSEE) chelators, were prepared by peptide synthesis and labelled with 99mTc. The tumour-targeting capacity of these conjugates was compared with each other and with the best previously available conjugate, 99mTc-maEEE-ZHER2:342, in nude mice bearing SKOV-3 xenografts. The tumour-targeting capacity of the most promising conjugate, 99mTc-maESE-ZHER2:342, was compared with radioiodinated ZHER2:342. Results  All novel conjugates demonstrated successful tumour targeting and a low degree of hepatobiliary excretion. The renal uptakes of serine-containing conjugates, 33 ± 5, 68 ± 21 and 71 ± 10%IA/g, for99mTc-maESE-ZHER2:342, 99mTc-maEES-ZHER2:342 and 99mTc-maSEE-ZHER2:342, respectively, were significantly reduced in comparison with 99mTc-maEEE-ZHER2:342 (102 ± 13%IA/g). For 99mTc-maESE-ZHER2:342, a tumour uptake of 9.6 ± 1.8%IA/g and a tumour-to-blood ratio of 58 ± 6 were reached at 4 h p.i. Conclusions  A combination of serine and glutamic acid residues in the chelator sequence confers increased renal excretion and relatively low renal uptake of 99mTc-labelled Affibody molecules. In combination with preserved targeting capacity, this improved imaging of targets in abdominal area.
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19.
  • Engfeldt, Torun, et al. (författare)
  • 99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule
  • 2007
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 34:11, s. 1843-1853
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z(HER2:342) binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z(HER2:342) with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with (99m)Tc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z(HER2:342) can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. METHODS: The Affibody molecule Z(HER2:342), carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D: -seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with (99m)Tc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of (99m)Tc-maSSS-Z(HER2:342) was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z(HER2:342). RESULTS: A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of (99m)Tc-maSSS-Z(HER2:342) was 11.5 +/- 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z(HER2:342) were better than those of radioiodinated Z(HER2:342). CONCLUSION: The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z(HER2:342) compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.
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20.
  • Engfeldt, Torun, et al. (författare)
  • Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence
  • 2007
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 34:5, s. 722-733
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Expression of human epidermal growth factor receptor type 2 (HER2) in malignant tumours possesses well-documented prognostic and predictive value. Non-invasive imaging of expression can provide valuable diagnostic information, thereby influencing patient management. Previously, we reported a phage display selection of a small (about 7 kDa) protein, the Affibody molecule Z(HER2:342), which binds HER2 with subnanomolar affinity, and demonstrated the feasibility of targeting of HER2-expressing xenografts using radioiodinated Z(HER2:342). The goal of this study was to develop a method for (99m)Tc labelling of Z(HER2:342) using the MAG3 chelator, which was incorporated into Z(HER2:342) using peptide synthesis, and evaluate the targeting properties of the labelled conjugate. METHODS: MAG3-Z(HER2:342) was assembled using Fmoc/tBu solid phase peptide synthesis. Biochemical characterisation of the agent was performed using RP-HPLC, ESI-MS, biosensor studies and circular dichroism. A procedure for (99m)Tc labelling in the presence of sodium/potassium tartrate was established. Tumour targeting was evaluated by biodistribution study and gamma camera imaging in xenograft-bearing mice. Biodistribution of (99m)Tc-MAG3-Z(HER2:342) and (125)I-para-iodobenzoate -Z(HER2:342) was compared 6 h p.i. RESULTS: Synthetic MAG3-Z(HER2:342) possessed an affinity of 0.2 nM for HER2 receptors. The peptide was labelled with (99m)Tc with an efficiency of about 75-80%. Labelled (99m)Tc-MAG3-Z(HER2:342) retained capacity to bind specifically HER2-expressing SKOV-3 cells in vitro. (99m)Tc-MAG3-Z(HER2:342) showed specific tumour targeting with a contrast similar to a radioiodinated analogue in mice bearing LS174T xenografts. Gamma camera imaging demonstrated clear and specific visualisation of HER2 expression. CONCLUSION: Incorporation of a mercaptoacetyl-containing chelating sequence during chemical synthesis enabled site-specific (99m)Tc labelling of the Z(HER2:342) Affibody molecule with preserved targeting capacity.
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21.
  • Eriksson, Annika K., et al. (författare)
  • Effects of A-site substitution on the structure and magnetic properties of Bi0.15Sr0.85-yAeyCo1-xFexO3-? perovskites
  • 2009
  • Ingår i: Solid State Sciences. - 1293-2558 .- 1873-3085. ; 11:11, s. 1945-1954
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of partial substitution of Sr2+ by Ca2+ and Ba2+ on the A-site of oxygen deficient perovskites, Bi0.15Sr0.85-yAeyCo1-xFexO3-?, where y = 0.29 for Ae = Ba and y = 0.17 for Ae =  Ca, and 0.0 ? x ? 1.0, have been investigated. The differing ionic size of the Ca2+ and Ba2+ cations influences both the crystal structure and the properties of the materials. The smaller Ca2+ cation favoured formation of an oxygen vacancy ordered perovskite superstructure (I4/mmm, a = 2ap, c = 4ap), meanwhile the presence of the larger Ba2+ cation promoted a disordered simple cubic structure (Pm-3m, a = ap) that was also found for all Fe containing samples, i.e. x ? 0.25. The samples were studied with PXRD, NPD, TGA, HREM and magnetic susceptibility measurements. All as-prepared samples exhibited long range G-type antiferromagnetic ordering. The effect of oxygen annealing was dramatic for the Bi0.15Sr0.68Ca0.17Co1-xFexO3-? series with a disappearance of magnetic order for x ? 0.25 linked to increasing spin glass properties. The oxygen content of the Bi0.15Sr0.56Ba0.29Co1-xFexO3-? as-prepared materials was generally higher than their Ca substituted counterparts, and the long range antiferromagnetic order was more resistant to oxygen annealing.
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22.
  • Evans Axelsson, Susan, et al. (författare)
  • Preclinical evaluation of (111)In-DTPA-INCA-X anti-Ku70/Ku80 monoclonal antibody in prostate cancer.
  • 2014
  • Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 4:4, s. 311-323
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this investigation was to assess the Ku70/Ku80 complex as a potential target for antibody imaging of prostate cancer. We evaluated the in vivo and ex vivo tumor targeting and biodistribution of the (111)In-labeled human internalizing antibody, INCA-X ((111)In-DTPA-INCA-X antibody), in NMRI-nude mice bearing human PC-3, PC-3M-Lu2 or DU145 xenografts. DTPA-conjugated, non-labeled antibody was pre-administered at different time-points followed by a single intravenous injection of (111)In-DTPA-INCA-X. At 48, 72 and 96 h post-injection, tissues were harvested, and the antibody distribution was determined by measuring radioactivity. Preclinical SPECT/CT imaging of mice with and without the predose was performed at 48 hours post-injection of labeled DTPA-INCA-X. Biodistribution of the labeled antibody showed enriched activity in tumor, spleen and liver. Animals pre-administered with DTPA-INCA-X showed increased tumor uptake and blood content of (111)In-DTPA-INCA-X with reduced splenic and liver uptake. The in vitro and in vivo data presented show that the (111)In-labeled INCA-X antibody is internalized into prostate cancer cells and by pre-administering non-labeled DTPA-INCA-X, we were able to significantly reduce the off target binding and increase the (111)In-DTPA-INCA-X mAb uptake in PC-3, PC-3M-Lu2 and DU145 xenografts. The results are encouraging and identifying the Ku70/Ku80 antigen as a target is worth further investigation for functional imaging of prostate cancer.
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23.
  • Evertsson, Maria, et al. (författare)
  • Combined Magnetomotive ultrasound, PET/CT, and MR imaging of (68)Ga-labelled superparamagnetic iron oxide nanoparticles in rat sentinel lymph nodes in vivo
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff. This study investigates a hypothetical clinical scenario of pre-operative PET imaging, combined with intra-operative MMUS imaging, implemented in a sentinel lymph node (SLN) rat model. At one-hour post injection of (68)Ga-labelled magnetic nanoparticles, six animals were imaged with combined PET/CT. After two or four days, the same animals were imaged with MMUS. In addition, ex-vivo MRI was used to evaluate the amount of nanoparticles in each single SLN. All SLNs were detectable by PET. Four out of six SLNs could be detected with MMUS, and for these MMUS and MRI measurements were in close agreement. The MRI measurements revealed that the two SLNs undetectable with MMUS contained the lowest nanoparticle concentrations. This study shows that MMUS can complement standard pre-operative imaging by providing bedside real-time images with high spatial resolution.
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24.
  • Girard, Maxime, et al. (författare)
  • Human-aided dispersal and population bottlenecks facilitate parasitism escape in the most invasive mosquito species
  • 2024
  • Ingår i: PNAS NEXUS. - : Oxford University Press. - 2752-6542. ; 3:5
  • Tidskriftsartikel (refereegranskat)abstract
    • During biological invasion process, species encounter new environments and partially escape some ecological constraints they faced in their native range, while they face new ones. The Asian tiger mosquito Aedes albopictus is one of the most iconic invasive species introduced in every inhabited continent due to international trade. It has also been shown to be infected by a prevalent yet disregarded microbial entomoparasite Ascogregarina taiwanensis. In this study, we aimed at deciphering the factors that shape the global dynamics of A. taiwanensis infection in natural A. albopictus populations. We showed that A. albopictus populations are highly colonized by several parasite genotypes but recently introduced ones are escaping it. We further performed experiments based on the invasion process to explain such pattern. To that end, we hypothesized that (i) mosquito passive dispersal (i.e. human-aided egg transportation) may affect the parasite infectiveness, (ii) founder effects (i.e. population establishment by a small number of mosquitoes) may influence the parasite dynamics, and (iii) unparasitized mosquitoes are more prompt to found new populations through active flight dispersal. The two first hypotheses were supported as we showed that parasite infection decreases over time when dry eggs are stored and that experimental increase in mosquitoes' density improves the parasite horizontal transmission to larvae. Surprisingly, parasitized mosquitoes tend to be more active than their unparasitized relatives. Finally, this study highlights the importance of global trade as a driver of biological invasion of the most invasive arthropod vector species.
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25.
  • Khoa, Nguyen Manh, et al. (författare)
  • Compounds from aerial parts of Isodon lophanthoides and their effects of cytotoxicity and LPS-induced IL-1β and IL-10 production in RAW 264.7 macrophages
  • Ingår i: Vietnam Journal of Chemistry. - 2572-8288.
  • Tidskriftsartikel (refereegranskat)abstract
    • The bioassay-guided isolation of compounds from the aerial parts of Isodon lophanthoides (IL) resulted in the identification of five compounds (1–5). The chemical structures of 1–5 were determined through spectral analyses and compared to those identified in the literature to be 4-hydroxybenzoic acid (1), protocatechuic acid (2), rosmarinic acid (3), coetsoidin B (4), and coetsoidin A (5). Compounds 1, 4, and 5 were found for the first time in the aerial parts of IL. Compounds 1 and 2 displayed potent cytotoxic activity against A549, MCF-7, HepG2, and HL60 cancer cell lines, with IC50 values ranging from 13.93 to 18.69 µm and from 11.97 to 18.30 µm, respectively. Compounds 1‒5 significantly inhibited LPS-induced IL-1β production in RAW 264.7 macrophages compared to the LPS 5 ng/mL control group, resulting in IL-1β concentrations ranging from 34.92 to 46.91 pg/mL. Additionally, compounds 1‒5 exhibited notable stimulation of IL-10 production, with IL-10 levels ranging from 358.77 to 478.23 pg/mL, compared to the LPS 5 ng/mL control group. These findings highlight the potential of compounds 1‒5 and the IL extracts for the cytotoxic effects on cancer cell lines and on LPS-induced IL-1β and IL-10 production in RAW 264.7 macrophages.
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26.
  • Kristiansson, Amanda, et al. (författare)
  • Protection of Kidney Function with Human Antioxidation Protein α 1 -Microglobulin in a Mouse 177 Lu-DOTATATE Radiation Therapy Model
  • 2019
  • Ingår i: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1523-0864 .- 1557-7716. ; 30:14, s. 1746-1759
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α 1 -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 ( 177 Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177 Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177 Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment. © Amanda Kristiansson et al. 2018; Published by Mary Ann Liebert, Inc.
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27.
  • Madru, Renata, et al. (författare)
  • (68)Ga-labeled superparamagnetic iron oxide nanoparticles (SPIONs) for multi-modality PET/MR/Cherenkov luminescence imaging of sentinel lymph nodes.
  • 2014
  • Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 4:1, s. 60-69
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to develop (68)Ga-SPIONs for use as a single contrast agent for dynamic, quantitative and high resolution PET/MR imaging of Sentinel Lymph Node (SLN). In addition (68)Ga enables Cherenkov light emission which can be used for optical guidance during resection of SLN. SPIONs were labeled with (68)Ga in ammonium acetate buffer, pH 5.5. The labeling yield and stability in human serum were determined using instant thin layer chromatography. An amount of 0.07-0.1 mL (~5-10 MBq, 0.13 mg Fe) of (68)Ga-SPIONs was subcutaneously injected in the hind paw of rats. The animals were imaged at 0-3 h and 25 h post injection with PET/CT, 9.4 T MR and CCDbased Cherenkov optical systems. A biodistribution study was performed by dissecting and measuring the radioactivity in lymph nodes, kidneys, spleen, liver and the injection site. The labeling yield was 97.3 ± 0.05% after 15 min and the (68)Ga-SPIONs were stable in human serum. PET, MR and Cherenkov luminescence imaging clearly visualized the SLN. Biodistribution confirmed a high uptake of the (68)Ga-SPIONs within the SLN. We conclude that generator produced (68)Ga can be labeled to SPIONs. Subcutaneously injected (68)Ga-SPIONs can enhance the identification of the SLNs by combining sensitive PET and high resolution MR imaging. Clinically, hybrid PET/MR cameras are already in use and (68)Ga-SPIONs have a great potential as a single-dose, tri-modality agent for diagnostic imaging and potential Cherenkov luminescent guided resection of SLN.
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28.
  • Mallapura, Hemantha, et al. (författare)
  • Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC using the cassette-based iMiDEVâ„¢ microfluidic radiosynthesizer
  • 2023
  • Ingår i: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The demand for Ga-68-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, Ga-68-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([Ga-68]Ga-FAPI-46) in late-phase studies, whereas [Ga-68]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.Results Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 +/- 5% for [Ga-68]Ga-FAPI-46 and 46 +/- 7% for [Ga-68]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC were 98.2 +/- 0.2% and 98.4 +/- 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including Ga-68 trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.Conclusions The microfluidic-based approach enabled the implementation of radiosynthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC on the iMiDEV (TM) microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2-3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [Ga-68]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.
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29.
  • Mellhammar, Emma, et al. (författare)
  • An attenuation method for reducing count rate losses in preclinical PET during intratherapeutic imaging
  • 2017
  • Ingår i: 2016 IEEE Nuclear Science Symposium, Medical Imaging Conference and Room-Temperature Semiconductor Detector Workshop, NSS/MIC/RTSD 2016. - 9781509016426 ; 2017-January
  • Konferensbidrag (refereegranskat)abstract
    • In pre-clinical imaging, tumor response to radionuclide therapy can be monitored with PET imaging. Radionuclides used for therapy such as 177Lu emit a significant amount of low energy photons. These photons may have an energy high enough to penetrate the imaged object and are the prone to be detected. Although these phtons are likely to be rejected electronically, they add dead-time to the system since they need to be processed by the electronics. This is a problem in high-sensitivity pre-clinical PET system with a low number of readout channels, such as the Genisys G8 investigated in this work. The low energy gammas may also affect image quality due to increased probability of pulse pile-up. The use of high-attenuating shields designed to absorb most of the low energy photons emitted from the therapeutic radionuclide were investigated. Cylindrical led shields were constructed with thicknesses between 1 and 3 mm. A 3mm thick cylindrical shield was also constructed out of Rose metal (50% Bi, 28% Pb, and 22% Sn). The diameter of the shield was wide enough to accommodate a NEMA IQ phantom and a mouse. The attenuation of the shields for annihilation radiation was measured with a 22Na point source placed at the center of the FOV. Measurements of the coincidence rate were performed with the lead shields in place. At a of thicknesses of 1 and 3mm, the coincidence rate was reduced by a factor or 0.70 and 0.40, respectively. To study the effect of the presence of a background of low energy gammas on the coincidence count rate and the efficacy of the lead shields, 177Lu was added to a 1 cm diameter hollow sphere. In the presence of 100 MBq of 177Lu, the coincidence count rate was reduced by a factor 0.20 due to the detector dead-time. Although the count rate was reduced by a factor of 0.40 with the 3mm shield around the source, the dead-time effects due to the 177Lu background were less than 7%. 18F imaging of a NEMA phantom and a tumor bearing mouse showed dramatic image distortions in the presence of the 177Lu background. When imaging of with the 3mm shield in place, the image distortions were eliminated and were comparable in to the images acquired without the background activity.
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30.
  • Nguyen, Thi Ngoc Phuong, 1993, et al. (författare)
  • Individual-, social- and policy- factors associated with smoking cessation among adult male cigarette smokers in Hanoi, Vietnam: a longitudinal study
  • 2023
  • Ingår i: BMC PUBLIC HEALTH. - : BioMed Central (BMC). - 1471-2458. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundNearly one-in-two Vietnamese men smoke cigarettes placing them among the highest tobacco consumers in the world. Despite the need for smoking cessation to curb the burden of tobacco-related diseases in Vietnam, this rate remains at less than 30%. Therefore, this study examines individual-, social- and policy factors associated with smoking cessation among adult male smokers in Vietnam.MethodsWe established a longitudinal International Tobacco Control study of male smokers in Hanoi, Vietnam, in September 2018. This paper analyses 1525 men who participated in baseline and one-year follow-up. We applied a weighted multivariable logistic regression to examine the association between smoking cessation and individual-, social- and policy predictors.ResultsAt follow-up, 14.8% of participants had quit smoking for at least 30 consecutive days during the last year. Among the persistent smokers, 56.6% expressed intention to quit smoking. Factors associated with smoking cessation included a lower number of cigarettes smoked per day (aOR = 0.96, 95% CI: 0.94, 0.99) and having several attempts to quit smoking (aOR = 2.16, 95% CI 1.13, 4.12). Intention to quit smoking was associated with multiple quit attempts, a chronic condition diagnosis, more tobacco-related knowledge, greater self-efficacy, and more worries about their future health. The perceived impact of smoke-free policy and health warning labels were positively associated with intention to quit at any stage.ConclusionsInterventions aimed at increasing smoking cessation should focus on all aspects of individual, social, and policy factors. Persistent smokers are more motivated to quit if they have made multiple quit attempts, more self-efficacy of quitting and worried about their future health, indicating that increasing smokers' beliefs and knowledge may be important for behavioural change. Health warning labels and tobacco taxation policies should be maintained and promoted as they are perceived to be particularly useful for persistent smokers' intention to quit.
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31.
  • Nguyen, Xuan Thi Thanh, et al. (författare)
  • Assessment of aflatoxin B \textlesssub\textgreater1\textless/sub\textgreater in maize and awareness of aflatoxins in Son La, Vietnam
  • 2018
  • Ingår i: Infection Ecology & Epidemiology. - : Taylor & Francis. - 2000-8686. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACTAflatoxin B1 (AFB1) is a fungal by-product which causes acute and chronic toxicity in humans and many other animals. This research was conducted to evaluate the prevalence of AFB1 contamination in maize and residents’ awareness of aflatoxins in Son La province, Vietnam. Maize samples were randomly collected from Son La province using multi-stage sampling. We used cut-off levels of 5 and 20 μg/kg and calculated the mean, median and range for each district. In addition, a questionnaire collected information from households about their knowledge, attitude and practice related to moldy maize. Out of 378 maize samples from Son La, 204 (54.0%) and 141 (37.3%) were contaminated with AFB1 at more than 5 µg/kg and 20 µg/kg, respectively. Mai Son district had the highest proportion of samples (54.0%) using a cut-off level \textgreater 20 µg/kg, and Yen Chau district the lowest (4%). People from the Thai ethnic group were 30.9 times more likely to consume meat from animals fed moldy maize than people from the Kinh ethn...
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32.
  • Norell, Derrick, et al. (författare)
  • Versatile in vitro system to study translocation and functional integration of bacterial outer membrane proteins
  • 2014
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 5396-
  • Tidskriftsartikel (refereegranskat)abstract
    • Gram-negative bacteria use the type-V secretion pathway to expose proteins at their cell surface, many of which have virulence functions. Translocation of those proteins across the outer membrane occurs either by means of dedicated translocator proteins (two-partner secretion) or covalently fused translocator domains (autotransporters). Translocator proteins and translocator domains are beta-barrels requiring the beta-barrel assembly machinery (BAM) for membrane integration. However, the molecular details of their passage across the envelope and insertion into the outer membrane remain enigmatic, owing in part to the fact that in vitro systems are not available. Here we describe a versatile in vitro reconstitution system that faithfully reproduces both branches of the type-V secretion pathway and the assembly of beta-barrel outer membrane proteins. This system will allow an in-depth analysis of protein secretion across and integration into outer membranes.
  •  
33.
  • Orlova, Anna, et al. (författare)
  • Pre-clinical evaluation of [111In]-benzyl-DOTA-Z(HER2:342), a potential agent for imaging of HER2 expression in malignant tumors
  • 2007
  • Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 20:3, s. 397-404
  • Tidskriftsartikel (refereegranskat)abstract
    • Imaging of expression of human epidermal growth factor receptor type 2 (HER2) in breast carcinomas may help to select patients eligible for trastuzumab therapy. The Affibody molecule Z(HER2:342) is a small (7-kDa) non-immunoglobulin affinity protein, which binds to HER2 with a picomolar affinity. Previously, a benzyl-DTPA conjugate of Z(HER2:342) was labeled with 111In and demonstrated good targeting in murine xenografts. We considered that the use of the macrocyclic chelator DOTA could increase the label stability and enhance a choice of nuclides, which could be used as a label for Z(HER2:342). The goal of this study was the preparation and pre-clinical evaluation of the indium-111- labeled DOTA-derivative of Z(HER2:342). Isothiocyanate-benzyl-DOTA was coupled to recombinant Z(HER2:342), and the conjugate was efficiently labeled with 111In at 60 degrees C. The specificity of 111In-benzyl-DOTA-Z(HER2:342) binding to HER2 was confirmed in vitro using HER2-expressing breast carcinoma BT474 and ovarian carcinoma SKOV-3 cell lines. Biodistribution of 111In-benzyl-DOTA-Z(HER2:342) was performed in nude mice bearing LS174T xenografts and compared directly with the biodistribution of 111In-benzyl-DTPA-Z(HER2:342). In vivo, 111In-benzyl-DOTA-Z(HER2:342) demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of 111In-benzyl-DOTA-Z(HER2:342) (4.4+/-1.0% IA/g) was specific and the tumor-to-blood ratio was 23. The use of benzyl-DTPA provided higher tumor-to-blood and tumor-to-liver ratios. gamma-camera imaging showed clear visualization of HER2-expressing xenografts using 111In-benzyl-DOTA-Z(HER2:342). 111In-benzyl-DOTA-Z(HER2:342) has a potential for imaging of HER2 expression in malignant tumors.
  •  
34.
  • Orlova, Anna, et al. (författare)
  • Re-186-maSGS-Z(HER2:342), a potential Affibody conjugate for systemic therapy of HER2-expressing tumours
  • 2010
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 37:2, s. 260-269
  • Tidskriftsartikel (refereegranskat)abstract
    • Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z(HER2:342) has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for Tc-99m-labelling, we have found that synthetic Z(HER2:342) conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. maGGG-Z(HER2:342) and maGSG-Z(HER2:342) were labelled with Re-186 and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by Re-186-maGSG-Z(HER2:342) were studied. Gluconate-mediated labelling of maGGG-Z(HER2:342) and maGSG-Z(HER2:342) with Re-186 provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both Re-186-maGGG-Z(HER2:342) and Re-186-maGSG-Z(HER2:342) demonstrated lower renal uptake than their Tc-99m-labelled counterparts. Re-186-maGSG-Z(HER2:342) provided the lowest uptake in healthy tissues. Biodistribution of Re-186-maGSG-Z(HER2:342) in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84 +/- 0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.
  •  
35.
  • Orlova, Anna, et al. (författare)
  • Synthetic affibody molecules : a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors
  • 2007
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:5, s. 2178-2186
  • Tidskriftsartikel (refereegranskat)abstract
    • The Affibody molecule Z(HER2:342-pep2), site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-Z(HER2:342-pep2) folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of (111)In was achieved within 30 min at low (room temperature) and high temperatures (up to 90 degrees C). Tumor uptake of (111)In-DOTA-Z(HER2:342-pep2) was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of >7.5, and high-contrast gamma camera images were obtained already 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of (111)In-DOTA-Z(HER2:342-pep2) obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-Z(HER2:342-pep2) has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.
  •  
36.
  • Phu, Vu Dinh, et al. (författare)
  • Ventilator-associated respiratory infection in a resource-restricted setting: impact and etiology
  • 2017
  • Ingår i: Journal of Intensive Care. - : BioMed Central (BMC). - 2052-0492. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • Ventilator-associated respiratory infection (VARI) is a significant problem in resource-restricted intensive care units (ICUs), but differences in casemix and etiology means VARI in resource-restricted ICUs may be different from that found in resource-rich units. Data from these settings are vital to plan preventative interventions and assess their cost-effectiveness, but few are available.
  •  
37.
  • Quang-Thuy, Ha, et al. (författare)
  • A Bisimulation-based Method of Concept Learning for Knowledge Bases in Description Logics
  • 2012
  • Ingår i: SoICT 2012 - 3rd International Symposium on Information and Communication Technology. - New York, New York, USA : ACM Press. ; , s. 241-249
  • Konferensbidrag (refereegranskat)abstract
    • We develop the first bisimulation-based method of concept learning, called BBCL, for knowledge bases in description logics (DLs). Our method is formulated for a large class of useful DLs, with well-known DLs like ALC, SHIQ, SHOIQ, SROIQ. As bisimulation is the notion for characterizing indis-cernibility of objects in DLs, our method is natural and very promising.
  •  
38.
  •  
39.
  • Qvarnström, O. Fredrik, et al. (författare)
  • Effects of affinity on binding of HER2-targeting Affibody molecules : Model experiments in breast cancer spheroids
  • 2011
  • Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 39:2, s. 353-359
  • Tidskriftsartikel (refereegranskat)abstract
    • Binding of a targeting agent in tumor tissue is influenced by many factors such as molecular weight, charge and affinity of the targeting agent and vascularization of the tumor. In this study, we analyzed tumor cell binding of three HER2-specific and radiolabeled Affibody molecules with different affinities. The Affibody molecules had affinities in the range of 0.12-3.8 nM. Cellular binding was analyzed, after 2 h of incubation, in tumor spheroids composed of BT474 breast cancer cells, which highly express HER2. Binding was, due to the binding-site barrier,limited to the outer 15 +/- 5 mu m rim of the spheroids, independent of affinity when the concentration of the substances was low. When the concentration was high, the binding site barrier was overcome and the binding occurred approximately 35 +/- 5 mu m into the spheroids for the two high affinity substances and 50 +/- 5 mu m for the low affinity substance. The lower affinity might allow for penetration into deeper regions due to less firm binding. We conclude that there is a binding site barrier within tumor spheroids which can be overcome by increased concentration of substance and modified by affinity.
  •  
40.
  • Shahid, Muhammad, et al. (författare)
  • Assessing the potential and hydrological usefulness of the CHIRPS precipitation dataset over a complex topography in Pakistan
  • 2021
  • Ingår i: Hydrological Sciences Journal. - : Informa UK Limited. - 0262-6667 .- 2150-3435. ; 66:11, s. 1664-1684
  • Tidskriftsartikel (refereegranskat)abstract
    • This study evaluates the spatial and temporal performance of the Climate Hazard Group InfraRed Precipitation Satellite (CHIRPS) against Tropical Rainfall Measuring Mission (TRMM) Multi-Satellite Precipitation Analysis (TMPA) 3B42/3B43 v. 7 and Global Precipitation Measurement (GPM)-based Integrated Multi-Satellite Retrievals for GPM (IMERG V06), from 2000 to 2013. Several statistical metrics were used to assess the performance of CHIRPS over the Indus Basin, and its hydrological utility is also assessed using the Soil and Water Assessment Tool (SWAT). The Gilgit and Soan basins were selected for hydrological modelling. The results demonstrate the spatial and temporal dependency of CHIRPS, i.e. better performance was observed in the Lower Indus Basin (LIB) while poor performance was observed in the Upper Indus Basin (UIB). The hydrological assessment of CHIRPS revealed poor performance (overestimation of streamflow) across the Gilgit Basin during both calibration and validation periods. Satisfactory to good performance was obtained across the Soan Basin.
  •  
41.
  • Siikanen, Jonathan, et al. (författare)
  • A solid target system with remote handling of irradiated targets for PET cyclotrons.
  • 2014
  • Ingår i: Applied Radiation and Isotopes. - : Elsevier BV. - 0969-8043. ; 94, s. 294-301
  • Tidskriftsartikel (refereegranskat)abstract
    • A solid target system was developed for a PET cyclotron. The system is compatible with many different target materials in the form of foils and electroplated/sputtered targets which makes it useful for production of a wide variety of different PET radionuclides. The target material is manually loaded into the system. Remote handling of irradiated target material is managed with a pneumatic piston and a vacuum technique which allows the targets to be dropped into a shielded transport container. To test the target performance, proton irradiations (12.8MeV, 45μA) of monoisotopic yttrium foils (0.64mm, direct water cooling) were performed to produce (89)Zr. The yields were 2200±200MBq (1h, n=13) and 6300±65MBq (3h, n=3).
  •  
42.
  • Strand, Joanna, et al. (författare)
  • Humanization, radiolabeling and biodistribution studies of an igg1-type antibody targeting uncomplexed psa for theranostic applications
  • 2021
  • Ingår i: Pharmaceuticals. - : MDPI AG. - 1424-8247. ; 14:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.
  •  
43.
  • Thanh Hoan, Nguyen, et al. (författare)
  • Novel Time Series Bagging Based Hybrid Models for Predicting Historical Water Levels in the Mekong Delta Region, Vietnam
  • 2022
  • Ingår i: CMES - Computer Modeling in Engineering & Sciences. - : Tech Science Press. - 1526-1492 .- 1526-1506. ; 131:3, s. 1431-1449
  • Tidskriftsartikel (refereegranskat)abstract
    • Water level predictions in the river, lake and delta play an important role in flood management. Every year Mekong River delta of Vietnam is experiencing flood due to heavy monsoon rains and high tides. Land subsidence may also aggravate flooding problems in this area. Therefore, accurate predictions of water levels in this region are very important to forewarn the people and authorities for taking timely adequate remedial measures to prevent losses of life and property. There are so many methods available to predict the water levels based on historical data but nowadays Machine Learning (ML) methods are considered the best tool for accurate prediction. In this study, we have used surface water level data of 18 water level measurement stations of the Mekong River delta from 2000 to 2018 to build novel time-series Bagging based hybrid ML models namely: Bagging (RF), Bagging (SOM) and Bagging (M5P) to predict historical water levels in the study area. Performances of the Bagging-based hybrid models were compared with Reduced Error Pruning Trees (REPT), which is a benchmark ML model. The data of 19 years period was divided into 70:30 ratio for the modeling. The data of the period 1/2000 to 5/2013 (which is about 70% of total data) was used for the training and for the period 5/2013 to 12/2018 (which is about 30% of total data) was used for testing (validating) the models. Performance of the models was evaluated using standard statistical measures: Coefficient of Determination (R2), Root Mean Square Error (RMSE) and Mean Absolute Error (MAE). Results show that the performance of all the developed models is good (R2 > 0.9) for the prediction of water levels in the study area. However, the Bagging-based hybrid models are slightly better than another model such as REPT. Thus, these Bagging-based hybrid time series models can be used for predicting water levels at Mekong data.
  •  
44.
  • Thi Thuy, Tran, et al. (författare)
  • A simple and fast kinetic assay for phytases using phytic acid-protein complex as substrate.
  • 2011
  • Ingår i: Analytical Biochemistry. - : Elsevier BV. - 1096-0309 .- 0003-2697. ; 410:2, s. 177-184
  • Tidskriftsartikel (refereegranskat)abstract
    • Phytase (EC 3.1.3.-) hydrolyzes phytate (IP6) present in cereals and grains to release inorganic phosphate (Pi), thereby making it bioavailable. The most commonly used method to assay phytase, developed nearly a century ago, measures the Pi liberated from IP6. This traditional end point assay is time consuming and well known for its cumbersomeness in addition to requiring extra caution for handling the toxic regents used. This paper reports a simple, fast and nontoxic kinetic method adaptable for high through-put for assaying phytase using IP6-lysozyme as a substrate. The assay is based on the principle that IP6 forms stable turbid complexes with positively charged lysozyme in a wide pH range and hydrolysis of the IP6 in the complex is accompanied with a decrease in turbidity monitored at 600 nm. The turbidity decrease correlates well to the released Pi from IP6. This kinetic method was found useful in assaying histidine acid phytases, including 3- and 6-phytases, a class representing all commercial phytases, and alkaline ß-propeller phytase from Bacillus sp. The influences of temperature, pH, phosphate and other salts on the kinetic assay were examined. Salts including NaCl, CaCl2, and phosphate all showed a concentration-dependent interference.
  •  
45.
  • Thi Thuy, Tran, et al. (författare)
  • Site-directed mutagenesis of an alkaline phytase: Influencing specificity, activity and stability in acidic milieu
  • 2011
  • Ingår i: Enzyme and Microbial Technology. - : Elsevier BV. - 0141-0229. ; 49:2, s. 177-182
  • Tidskriftsartikel (refereegranskat)abstract
    • Site-directed mutagenesis of a thermostable alkaline phytase from Bacillus sp. MD2 was performed with an aim to increase its specific activity and activity and stability in an acidic environment. The mutation sites are distributed on the catalytic surface of the enzyme (P257R, E180N, E229V and S283R) and in the active site (K77R, K179R and E227S). Selection of the residues was based on the idea that acid active phytases are more positively charged around their catalytic surfaces. Thus, a decrease in the content of negatively charged residues or an increase in the positive charges in the catalytic region of an alkaline phytase was assumed to influence the enzyme activity and stability at low pH. Moreover, widening of the substrate-binding pocket is expected to improve the hydrolysis of substrates that are not efficiently hydrolysed by wild type alkaline phytase. Analysis of the phytase variants revealed that E229V and S283R mutants increased the specific activity by about 19% and 13%, respectively. Mutation of the active site residues K77R and K179R led to severe reduction in the specific activity of the enzyme. Analysis of the phytase mutant-phytate complexes revealed increase in hydrogen bonding between the enzyme and the substrate, which might retard the release of the product, resulting in decreased activity. On the other hand, the double mutant (K77R-K179R) phytase showed higher stability at low pH (pH 2.6-3.0). The E227S variant was optimally active at pH 5.5 (in contrast to the wild type enzyme that had an optimum pH of 6) and it exhibited higher stability in acidic condition. This mutant phytase, displayed over 80% of its initial activity after 3 h incubation at pH 2.6 while the wild type phytase retained only about 40% of its original activity. Moreover, the relative activity of this mutant phytase on calcium phytate, sodium pyrophosphate and p-nitro phenyl phosphate was higher than that of the wild type phytase. (C) 2011 Elsevier Inc. All rights reserved.
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46.
  • Thi Thuy, Tran, et al. (författare)
  • Thermostable alkaline phytase from Bacillus sp. MD2: Effect of divalent metals on activity and stability.
  • 2011
  • Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 105:7, s. 1000-1007
  • Tidskriftsartikel (refereegranskat)abstract
    • Phytate, the major source of phosphorus in seeds, exists as a complex with different metal ions. Alkaline phytases are known to dephosphorylate phytate complexed with calcium ions in contrast to acid phytases that act only on phytic acid. A recombinant alkaline phytase from Bacillus sp. MD2 has been purified and characterized with respect to the effect of divalent metal ions on the enzyme activity and stability. The presence of Ca(2+) on both the enzyme and the substrate is required for optimal activity and stability. Replacing Ca(2+) with Ba(2+), Mn(2+), Mg(2+) and Sr(2+) in the phytase resulted in the expression of >90% of the maximal activity with calcium-phytate as the substrate, while Fe(2+) and Zn(2+) rendered the enzyme inactive. On the other hand, the calcium loaded phytase showed significant activity (60%) with sodium phytate and lower activity (17-20%) with phytate complexed with only Mg(2+), Sn(2+) and Sr(2+), respectively. On replacing Ca(2+) on both the enzyme and the substrate with other metal ions, about 20% of the maximal phytase activity was obtained only with Mg(2+) and Sr(2+), respectively. Only Ca(2+) resulted in a marked increase in the melting temperature (T(m)) of the enzyme by 12-21°C, while Ba(2+), Mn(2+), Sr(2+) or Cu(2+) resulted in a modest (2-3.5°C) increase in T(m). In the presence of 1-5mM Ca(2+), the optimum temperature of the phytase activity was increased from 40°C to 70°C, while optimum pH of the enzyme shifted by 0.4-1 pH unit towards the acidic region.
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47.
  • Thi Thuy, Tran (författare)
  • Thermostable Phytase from a Bacillus sp.: Heterologous Production, Mutation, Characterization and Assay Development
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Phytase is an important enzyme in the food/feed industry. It catalyzes the hydrolysis of phytate, an anti-nutrient compound present in cereals and grains, to release orthophosphate and myo-inositol-6-phosphate with lower degrees of phosphorylation. Phytic acid is a strong chelator capable of complexing with a variety of metal ions under neutral and alkaline conditions, as well as with proteins and starch under acidic conditions. Treatment with phytase increases not only the bioavailability of inorganic phosphorus but also the digestibility of proteins. Moreover, it improves absorption of minerals from food/feed. The action of phytase also contributes towards reducing the pollution in surface- and ground water caused by the phytate and phosphorus run-off from manure in intensive livestock regions. All the commercially available phytases are histidine acid phytases with optimum activities at low pH and with low thermostabilities. Alkaline phytases (also called β-propeller phytases) are active at neutral or slightly alkaline conditions, calcium-dependent, and are quite thermostable so as to withstand the high temperatures during the pelleting of animal feeds. They can hence exhibit activities in the small intestine of animals as well as during storage of feeds. Alkaline phytases have several other potential applications. This thesis presents the studies on a phytase from Bacillus sp. MD2 isolated in Vietnam. The focus has been directed to (1) developing a new kinetic method to determine the phytase activity, (2) cloning, expression and production of the recombinant phytase from Bacillus sp. MD2, (3) the metal dependence of the catalytic properties and stability of the recombinant phytase, and (4) site-directed mutagenesis of the recombinant phytase to improve certain properties of the enzyme relevant for food/feed applications. A kinetic assay for phytases has been developed based on the turbidity reduction of phytate-protein complexes used as substrates. This method offered a reliable way to measure the enzyme activity of both histidine acid phytases and ß-propeller phytases. The method was found to be simpler, faster, and to measure the activity under conditions closer to those existing in the gastrointestinal tract of animals, thus making it more suitable for evaluating phytases for feed and food applications in comparison with the traditional method based on the release of phosphate from sodium phytate. The phytase gene from Bacillus sp. MD2 was cloned and expressed in Escherichia coli. Cultivation of the recombinant bacteria in a minimum medium using a fed-batch strategy combined with the control of the inorganic phosphate concentration resulted in a high level of production of the recombinant phytase. Lactose could be used as an alternative inducer to isopropyl-β-D-thiogalactoside, thus reducing the production cost. A significant amount of the expressed phytase (90% of the total active enzyme) leaked out into the medium, thereby facilitating the subsequent downstream processing. A close investigation of the effect of divalent metal ions on the activity and stability of the recombinant phytase was performed. Calcium played a critical role in stabilizing the enzyme and in activating the substrate (phytate) to fulfil the activity of the enzyme. Other metal ions (Ba2+, Mn2+, Mg2+ and Sr2+) could replace Ca2+ in the active site of the enzyme and recover more than 90% of the enzyme activity with the calcium complex substrate. On the other hand, the presence of Ca2+ on the phytate was crucial for an optimal expression of the phytase activity. The relationship between structure and function of the phytase was probed by site-directed mutagenesis. Single site mutations, S283R and E229V, on the catalytic surface increased the specific activity of the enzyme by 13 and 19%, respectively. Mutation of the catalytically important residue E227 to Ser shifted the optimum pH of the enzyme to the acidic side and simultaneously improved its acid stability. After 3 h of incubation at pH 2.6, the mutant phytase (E227S) retained over 80% of its initial activity while the wild-type phytase displayed only 40% of its original activity. Moreover, the E227S mutant phytase, unlike its wild-type, showed a higher relative activity towards calcium phytate, sodium pyrophosphate and p-nitro phenyl phosphate, thus suggesting a broader substrate specificity. Alkaline phytases have a lower specific activity than their acid counterparts. An increased knowledge of the enzymes for designing mutations to improve their specific activity and catalytic activity at low pH are thus necessary for rendering industrial applications possible.
  •  
48.
  • Thuy, Tran Thi, et al. (författare)
  • Discrimination between glycosylation patterns of therapeutic antibodies using a microfluidic platform, MALDI-MS and multivariate statistics
  • 2012
  • Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 70, s. 47-52
  • Tidskriftsartikel (refereegranskat)abstract
    • Optimal glycosylation with respect to the efficacy, serum half-life time, and immunogenic properties is essential in the generation of therapeutic antibodies. The glycosylation pattern can be affected by several different parameters during the manufacture of antibodies and may change significantly over cultivation time. Fast and robust methods for determination of the glycosylation patterns of therapeutic antibodies are therefore needed. We have recently presented an efficient method for the determination of glycans on therapeutic antibodies using a microfluidic CD platform for sample preparation prior to matrix-assisted laser-desorption mass spectrometry analysis. In the present work, this method is applied to analyse the glycosylation patterns of three commercially available therapeutic antibodies and one intended for therapeutic use. Two of the antibodies produced in mouse myeloma cell line (SP2/0) and one produced in Chinese hamster ovary (CHO) cells exhibited similar glycosylation patterns but could still be readily differentiated from each other using multivariate statistical methods. The two antibodies with most similar glycosylation patterns were also studied in an assessment of the method's applicability for quality control of therapeutic antibodies. The method presented in this paper is highly automated and rapid. It can therefore efficiently generate data that helps to keep a production process within the desired design space or assess that an identical product is being produced after changes to the process.
  •  
49.
  • Thuy, Tran Thi, et al. (författare)
  • Glycosylation Profiling of Therapeutic Antibodies in Serum Samples Using a Microfluidic CD Platform and MALDI-MS
  • 2013
  • Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 24:7, s. 1053-1063
  • Tidskriftsartikel (refereegranskat)abstract
    • The serum clearance rate of therapeutic antibodies is important as it affects the clinical efficacy, required dose, and dose frequency. The glycosylation of antibodies has in some studies been shown to have an impact on the elimination rates in vivo. Monitoring changes to the glycan profiles in pharmacokinetics studies can reveal whether the clearance rates of the therapeutic antibodies depend on the different glycoforms, thereby providing useful information for improvement of the drugs. In this paper, a novel method for glycosylation analysis of therapeutic antibodies in serum samples is presented. A microfluidic compact-disc (CD) platform in combination with MALDI-MS was used to monitor changes to the glycosylation profiles of samples incubated in vitro. Antibodies were selectively purified from serum using immunoaffinity capture on immobilized target antigens. The glycans were enzymatically released, purified, and finally analyzed by MALDI-TOF-MS. To simulate changes to glycan profiles after administration in vivo, a therapeutic antibody was incubated in serum with the enzyme alpha 1-2,3 mannosidase to artificially reduce the amount of the high mannose glycoforms. Glycan profiles were monitored at specific intervals during the incubation. The relative abundance of the high mannose 5 glycoform was clearly found to decrease and, simultaneously, that of high mannose 4 increased over the incubation period. The method can be performed in a rapid, parallel, and automated fashion for glycosylation profiling consuming low amounts of samples and reagents. This can contribute to less labor work and reduced cost of the studies of therapeutic antibodies glycosylation in vitro and in vivo.
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50.
  • Thuy, Tran Thi, et al. (författare)
  • Parallel sample preparation of proteins, from crude samples to crystals ready for MALDI-MS, in an integrated microfluidic system
  • 2010
  • Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 878:28, s. 2803-2810
  • Tidskriftsartikel (refereegranskat)abstract
    • A microfluidic structure is presented where selective capture of proteins in complex samples, followed by clean-up, enzymatic processing, and MALDI-MS sample preparation of peptides generated, can be performed. The structure uses an affinity column to capture the protein while all other components in the sample are disposed of. The protein of interest is then eluted from the affinity column and captured on a second column on which the enzymatic processing is performed. Salts and hydrophilic contaminants are then removed before the products from the enzymatic reaction are eluted together with a suitable MALDI matrix and the solvent evaporated in a designated MALDI target structure. All steps can be performed automatically in 54 parallel microstructures on a microfluidic compact disc. The process is demonstrated by the selective capture and tryptic digest of recombinant IgG molecules from samples containing other proteins: an excess of bovine serum albumin or spent cell culture media.
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