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5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.We employed the 14C-deoxyglucose autoradiographic method to map the activity in the cerebellar cortex of rhesus monkeys that performed forelimb movements either in the light or in the dark and of monkeys that observed forelimb movements executed by a human experimenter. The execution of forelimb movements, both in the light and in the dark, activated the forelimb representations in the cerebellar hemispheric extensions of 1) vermian lobules IV-VI and 2) vermian lobule VIIIB, ipsilaterally to the moving forelimb. Activations in the former forelimb representation involved both a paravermal and a lateral hemispheric region. Also, Crus II posterior in the ansiform lobule (the hemispheric expansion of lobule VIIB) was activated bilaterally by execution of movements in the light but not in the dark. Action observation activated the lateral-most region of the forelimb representation in the lateral hemispheric extension of vermian lobules IV-VI, as well as the crus II posterior, bilaterally. Our results demonstrate that the cerebellar cortex, in addition to its involvement in the generation of movement, is also recruited in the perception of observed movements. Mycophenolate mofetil Moreover, our findings suggest a modularity gradient in the primate cerebellar cortex, which progresses from unimodal (medially) to multimodal (laterally) functional areas.
Despite increasing interest in community-based advance care planning interventions, few studies investigate the societal impact of such initiatives. The DöBra cards, a Swedish adaptation of the GoWish cards, were first used for advance care planning conversations in a participatory action research project and later, due to popular demand, made available for purchase by the general public. We explore how the DöBra cards were disseminated and used publicly, to understand their impact in the community.
We used Ripple Effects Mapping to follow three dissemination ripples, based on interviews with 20 participants, analyzed with directed content analysis.
Key factors influencing dissemination of the DöBra cards included 'champions' with a mandate within their context or organization, policy documents including use of the cards, media coverage, and presentations of the cards in various settings. The DöBra cards were adapted for use individually and in groups in different private, professional, and organizationng and death was brought to agendas in new contexts.
Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma.
Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible.
All patients with a somatic
mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radithe growth velocity is possible.
Although IDH-mutant tumors aggregate to the frontotemporal regions, the clustering pattern of IDH-wildtype tumors is less clear. As voxel-based lesion-symptom mapping (VLSM) has several limitations for solid lesion mapping, a new technique, whole-lesion phenotype analysis (WLPA), is developed. We utilize WLPA to assess spatial clustering of tumors with IDH mutation from The Cancer Genome Atlas and The Cancer Imaging Archive.
The degree of tumor clustering segmented from T1 weighted images is measured to every other tumor by a function of lesion similarity to each other via the Hausdorff distance. Each tumor is ranked according to the degree to which its neighboring tumors show identical phenotypes, and through a permutation technique, significant tumors are determined. VLSM was applied through a previously described method.
A total of 244 patients of mixed-grade gliomas (WHO II-IV) are analyzed, of which 150 were IDH-wildtype and 139 were glioblastomas. VLSM identifies frontal lobe regions that are more likely associated with the presence of IDH mutation but no regions where IDH-wildtype was more likely to be present. WLPA identifies both IDH-mutant and -wildtype tumors exhibit statistically significant spatial clustering.
WLPA may provide additional statistical power when compared with VLSM without making several potentially erroneous assumptions. WLPA identifies tumors most likely to exhibit particular phenotypes, rather than producing anatomical maps, and may be used in conjunction with VLSM to understand the relationship between tumor morphology and biologically relevant tumor phenotypes.
WLPA may provide additional statistical power when compared with VLSM without making several potentially erroneous assumptions. WLPA identifies tumors most likely to exhibit particular phenotypes, rather than producing anatomical maps, and may be used in conjunction with VLSM to understand the relationship between tumor morphology and biologically relevant tumor phenotypes.
Currently, bevacizumab (BEV), an antiangiogenic agent, is used as an adjunctive therapy to re-irradiation and surgery in patients with recurrent high-grade gliomas (rHGG). BEV has shown to decrease enhancement on MRI, but it is often unclear if these changes are due to tumor response to BEV or treatment-induced changes in the blood brain barrier. Preliminary studies show that amino acid PET can aid in distinguishing these changes on MRI.
The authors performed a systematic review of PubMed and Embase through July 2020 with the search terms 'bevacizumab' or 'Avastin' and 'recurrent glioma' and 'PET,' yielding 38 papers, with 14 meeting inclusion criteria.
Thirteen out of fourteen studies included in this review used static PET and three studies used dynamic PET to evaluate the use of BEV in rHGG. Six studies used the amino acid tracer [18F]FET, four studies used [11C]MET, and four studies used [18F]FDOPA.
[18F]FET, [11C]MET, and [18F]FDOPA PET in combination with MRI have shown promising results for improving accuracy in diagnosing tumor recurrence, detecting early treatment failure, and distinguishing between tumor progression and treatment-induced changes in patients with rHGG treated with BEV.
[18F]FET, [11C]MET, and [18F]FDOPA PET in combination with MRI have shown promising results for improving accuracy in diagnosing tumor recurrence, detecting early treatment failure, and distinguishing between tumor progression and treatment-induced changes in patients with rHGG treated with BEV.
Urinary tract infections are common and are increasingly resistant to antibiotic therapy. Northern Australia is a sparsely populated region with limited access to healthcare, a relatively high burden of disease, a substantial regional and remote population, and high rates of antibiotic resistance in skin pathogens.
To explore trends in antibiotic resistance for common uropathogens
and
in northern Australia, and how these relate to current treatment guidelines in the community and hospital settings.
We used data from an antibiotic resistance surveillance system. We calculated the monthly and yearly percentage of isolates that were resistant in each antibiotic class, by bacterium. We analysed resistance proportions geographically and temporally, stratifying by healthcare setting. Using simple linear regression, we investigated longitudinal trends in monthly resistance proportions and correlation between community and hospital isolates.
Our analysis included 177 223 urinary isolates from four pathoOur findings demonstrate the importance of local surveillance data (HOTspots) to inform clinical decision making and guidelines.Therapeutic hypothermia for hypoxic-ischaemic encephalopathy provides partial white matter protection. Recombinant erythropoietin reduces demyelination after hypoxia-ischaemia, but it is unclear whether adjunct erythropoietin treatment can further improve outcomes after therapeutic hypothermia. Term-equivalent fetal sheep received sham-ischaemia (n = 9) or cerebral ischaemia for 30 min (ischaemia-vehicle, n = 8), followed by intravenous infusion of recombinant erythropoietin (ischaemia-Epo, n = 8; 5000 IU/kg bolus dose, then 833.3 IU/kg/h), cerebral hypothermia (ischaemia-hypothermia, n = 8), or recombinant erythropoietin plus hypothermia (ischaemia-Epo-hypothermia, n = 8), from 3 to 72 h post-ischaemia. Foetal brains were harvested at 7 days after cerebral ischaemia. Ischaemia was associated with marked loss of total Olig2-positive oligodendrocytes with reduced density of myelin and linearity of the white matter tracts (P less then 0.01), and microglial induction and increased caspase-3-positive apoptosis. Cerebral hypothermia improved the total number of oligodendrocytes and restored myelin basic protein (P less then 0.01), whereas recombinant erythropoietin partially improved myelin basic protein density and tract linearity. Both interventions suppressed microgliosis and caspase-3 (P less then 0.05). Co-treatment improved 2',3'-cyclic-nucleotide 3'-phosphodiesterase-myelin density compared to hypothermia, but had no other additive effect. These findings suggest that although hypothermia and recombinant erythropoietin independently protect white matter after severe hypoxia-ischaemia, they have partially overlapping anti-inflammatory and anti-apoptotic effects, with little additive benefit of combination therapy.SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%).
