1,972 research outputs found
Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms
<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p>
<p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p>
<p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p>
β-Cell Generation: Can Rodent Studies Be Translated to Humans?
β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources of β cells. Islet regeneration in vivo and generation of β-cells ex vivo followed by transplantation represent attractive therapeutic alternatives to restore the β-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for future β-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (both ex vivo on primary cells and in vivo on animal models), when compared with clinical data and studies performed on human cells
Contrast-enhanced ultrasound as support for prostate brachytherapy treatment planning
Purpose: To investigate the possibility of localization of intraprostatic lesions (IL) with contrast-enhanced ultrasound (CEUS) to support the brachytherapy treatment planning of temporary implants. Material and methods: Two brachytherapy treatment plans were generated for 8 patients treated with external beam radiotherapy and pulsed-dose rate brachytherapy boost for prostate cancer. The first and second brachytherapy treatment plan was without and with knowledge of the localization of the ILs, respectively. Pairwise comparison was performed on prostate, rectum, and urethra dose-volume parameters and total reference air kerma (TRAK)-values. Results: Coverage of the ILs by the 140% isodose was increased from mean 66.0-67.7% for the standard plan to mean 92.5-95.7% for the adapted plan. The mean D90 of the ILs increased from 1.49-1.57 Gy/pulse to 1.76-1.81 Gy/pulse. Dose-volume parameters for the prostate, rectum, and urethra and the TRAK did not change. Conclusions: CEUS technique is a promising method for IL localization to aid in brachytherapy treatment planning. Dose coverage on the IL could be improved without any increase of dose in organs at ris
Advanced breast cancer and its prevention by screening.
In discussions on breast cancer screening, much attention has been focussed on the possible morbidity generated by screening. Favourable effects like the prevention of advanced disease seem underestimated, probably because quantification is that difficult. To analyse the amount of care and treatment given to women with advanced breast cancer, we report on patients followed from first recurrence until death using patient files and national sources. A random sample of 60 female cases from computerised registries of two cancer centres and a sample of 20 cases from a non-computerised hospital registry was taken. A total of 68 patient files were sufficiently documented. A woman with advanced breast cancer is estimated to have a 39% loss in utility compared to a healthy woman (range 27-45%). Hormonal treatment is the main modality during 14 and chemotherapy during 4 months. Total medical cost from diagnosis of advanced disease until death amounts to 17,100 US dollars, or 21,000 when including extramural cost. The effect of breast cancer screening by preventing the occurrence of advanced disease is quantified. The resulting gain in quality of life contributes 70% of the total gain in quality of life. In the long run, almost half of the annual cost of screening will be offset by savings in the cost for advanced disease. Only the changes in palliative surgery and/or radiotherapy will be small in contrast to primary treatment changes. Besides the mortality reduction, screening is justified by the improvements in quality of life and cost savings for women prevented from reaching advanced disease
Novel Point Mutation in the Extracellular Domain of the Granulocyte Colony-Stimulating Factor (G-Csf) Receptor in a Case of Severe Congenital Neutropenia Hyporesponsive to G-Csf Treatment
Severe congenital neutropenia (SCN) is a heterogeneous condition characterized by a drastic reduction in circulating neutrophils and a maturation arrest of myeloid progenitor cells in the bone marrow. Usually this condition can be successfully treated with granulocyte colony-stimulating factor (G-CSF). Here we describe the identification of a novel point mutation in the extracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who failed to respond to G-CSF treatment. When this mutant G-CSF-R was expressed in myeloid cells, it was defective in both proliferation and survival signaling. This correlated with diminished activation of the receptor complex as determined by signal transducer and activator of transcription (STAT) activation, although activation of STAT5 was more affected than STAT3. Interestingly, the mutant receptor showed normal affinity for ligand, but a reduced number of ligand binding sites compared with the wild-type receptor. This suggests that the mutation in the extracellular domain affects ligand–receptor complex formation with severe consequences for intracellular signal transduction. Together these data add to our understanding of the mechanisms of cytokine receptor signaling, emphasize the role of GCSFR mutations in the etiology of SCN, and implicate such mutations in G-CSF hyporesponsiveness
Umsetzung von Lungenkrebs-Screening
Two large-scale and sufficiently powered randomized-controlled trials and several smaller European trials have provided evidence on the effectiveness and feasibility of screening for lung cancer by means of low-dose computed tomography (LDCT) for a high-risk population. These findings support the implementation and upscaling of lung cancer screening to nationwide programs in Germany and the rest of Europe. At the same time, lung cancer screening efficiency can still be improved by further personalization and risk stratification, to maintain or improve the benefits while substantially reducing harms and costs (such as CT examinations needed, false-positive results and subsequent follow-up procedures). This review discusses the most pressing issues, such as the further development of adequate recruitment methods, risk-based eligibility and screening intervals, improved nodule detection and management, integrated smoking cessation programs, and a unified approach of the early detection of smoking-related diseases. The 4-IN-THE-LUNG-RUN (acronym for: Towards INdividually tailored INvitations, screening INtervals and INtegrated co-morbidity reducing strategies in lung cancer screening) is the first European multi-centred implementation trial on volume CT lung cancer screening amongst 24,000 high-risk subjects, across five countries. Germany is one of the participating countries, represented by the Deutsche Krebsforschungszentrum and the Universitätsklinikum (Ruhrlandklinik) Essen. The trial is expected to provide answers to the remaining issues, so that a high-quality screening program can be made accessible to those who might benefit most from lung cancer screening while keeping individual and societal harms at a minimum.</p
Umsetzung von Lungenkrebs-Screening
Two large-scale and sufficiently powered randomized-controlled trials and several smaller European trials have provided evidence on the effectiveness and feasibility of screening for lung cancer by means of low-dose computed tomography (LDCT) for a high-risk population. These findings support the implementation and upscaling of lung cancer screening to nationwide programs in Germany and the rest of Europe. At the same time, lung cancer screening efficiency can still be improved by further personalization and risk stratification, to maintain or improve the benefits while substantially reducing harms and costs (such as CT examinations needed, false-positive results and subsequent follow-up procedures). This review discusses the most pressing issues, such as the further development of adequate recruitment methods, risk-based eligibility and screening intervals, improved nodule detection and management, integrated smoking cessation programs, and a unified approach of the early detection of smoking-related diseases. The 4-IN-THE-LUNG-RUN (acronym for: Towards INdividually tailored INvitations, screening INtervals and INtegrated co-morbidity reducing strategies in lung cancer screening) is the first European multi-centred implementation trial on volume CT lung cancer screening amongst 24,000 high-risk subjects, across five countries. Germany is one of the participating countries, represented by the Deutsche Krebsforschungszentrum and the Universitätsklinikum (Ruhrlandklinik) Essen. The trial is expected to provide answers to the remaining issues, so that a high-quality screening program can be made accessible to those who might benefit most from lung cancer screening while keeping individual and societal harms at a minimum.</p
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