Endocytosis of therapeutic macromolecules in tumor cells - Mechanistic aspects of the proteoglycan receptor function

Novel therapeutics to combat cancer are urgently needed. Most current pharmacological therapies have severe side effects and are seldom curative. Macromolecular drugs, and in particular nucleic acid based drugs, offer a potential remedy for this situation. Currently, the absence of efficacious and safe methods to deliver nucleic acids to intracellular sites of action is the main impediment to the introduction of nucleic acid based therapies in the clinic. Viral delivery methods have been demonstrated to efficiently deliver nucleic acids, but also to be associated with severe, occasionally life threatening, immune reactions. Non-viral delivery methods are, so far, not sufficiently efficient for use in the clinic. Many viral and virtually all non-viral macromolecular delivery methods depend on cell surface heparan sulfate proteoglycans (HS PGs) for efficient uptake, however the details of this mechanism and the exact role of the PG has been unclear. The aim of this thesis was to clarify the role of the cell surface PG in macromolecular uptake processes. It is demonstrated that mammalian cells can internalize extracellular DNA by a pathway strictly dependent on cell surface PGs and this pathway is characterized. Secreted, positively charged, proteins and peptides including the antimicrobial peptide LL-37, are shown to facilitate the uptake process. It is also demonstrated that specific HS epitopes, present on cell surface HS PGs, are pivotal for the uptake of diverse HS binding ligands including polyamines and macromolecular antibody complexes. Finally, using a newly developed method for the isolation of endocytic vesicles, it is demonstrated that both classes of cell surface HS PGs, syndecans and glypicans, are true internalizing receptors capable of intracellular macromolecular delivery. This thesis advances our understanding of PGs as potential targets for macromolecular delivery vehicles. This understanding will be of aid for the development of future macromolecular drugs to the benefit of the patient

Global, regional, and national burden of other musculoskeletal disorders, 1990–2020, and projections to 2050:a systematic analysis of the Global Burden of Disease Study 2021

BACKGROUND: Musculoskeletal disorders include more than 150 different conditions affecting joints, muscles, bones, ligaments, tendons, and the spine. To capture all health loss from death and disability due to musculoskeletal disorders, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) includes a residual musculoskeletal category for conditions other than osteoarthritis, rheumatoid arthritis, gout, low back pain, and neck pain. This category is called other musculoskeletal disorders and includes, for example, systemic lupus erythematosus and spondylopathies. We provide updated estimates of the prevalence, mortality, and disability attributable to other musculoskeletal disorders and forecasted prevalence to 2050.METHODS: Prevalence of other musculoskeletal disorders was estimated in 204 countries and territories from 1990 to 2020 using data from 68 sources across 23 countries from which subtraction of cases of rheumatoid arthritis, osteoarthritis, low back pain, neck pain, and gout from the total number of cases of musculoskeletal disorders was possible. Data were analysed with Bayesian meta-regression models to estimate prevalence by year, age, sex, and location. Years lived with disability (YLDs) were estimated from prevalence and disability weights. Mortality attributed to other musculoskeletal disorders was estimated using vital registration data. Prevalence was forecast to 2050 by regressing prevalence estimates from 1990 to 2020 with Socio-demographic Index as a predictor, then multiplying by population forecasts.FINDINGS: Globally, 494 million (95% uncertainty interval 431-564) people had other musculoskeletal disorders in 2020, an increase of 123·4% (116·9-129·3) in total cases from 221 million (192-253) in 1990. Cases of other musculoskeletal disorders are projected to increase by 115% (107-124) from 2020 to 2050, to an estimated 1060 million (95% UI 964-1170) prevalent cases in 2050; most regions were projected to have at least a 50% increase in cases between 2020 and 2050. The global age-standardised prevalence of other musculoskeletal disorders was 47·4% (44·9-49·4) higher in females than in males and increased with age to a peak at 65-69 years in male and female sexes. In 2020, other musculoskeletal disorders was the sixth ranked cause of YLDs globally (42·7 million [29·4-60·0]) and was associated with 83 100 deaths (73 600-91 600).INTERPRETATION: Other musculoskeletal disorders were responsible for a large number of global YLDs in 2020. Until individual conditions and risk factors are more explicitly quantified, policy responses to this burden remain a challenge. Temporal trends and geographical differences in estimates of non-fatal disease burden should not be overinterpreted as they are based on sparse, low-quality data.FUNDING: Bill &amp; Melinda Gates Foundation.</p

Nanotubes, exosomes, and nucleic acid–binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease

The prevailing view that eukaryotic cells are restrained from intercellular exchange of genetic information has been challenged by recent reports on nanotubes, exosomes, apoptotic bodies, and nucleic acid–binding peptides that provide novel pathways for cell–cell communication, with implications in health and disease

Textaháls ,,TextNeck“ –Ný heilsufarsleg ógn eða heimagert vandamál?

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkin