Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood
; however, the reason for this is unclear. Here ...we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.
Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and ...early restricted progenitors
. LEPR
cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors
, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin
, distinguishes peri-arteriolar LEPR
cells poised to undergo osteogenesis from peri-sinusoidal LEPR
cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR
osteolectin
cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin
cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin
cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin
cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin
cells depleted osteolectin
cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing.
Deficits in executive functions (EFs), cognitive processes that control goal-directed behaviors, are associated with psychopathology and neurologic disorders. Little is known about the molecular ...bases of individual differences in EFs. Prior candidate gene studies have been underpowered in their search for dopaminergic processes involved in cognitive functioning, and existing genome-wide association studies of EFs used small sample sizes and/or focused on individual tasks that are imprecise measures of EFs.
We conducted a genome-wide association study of a common EF (cEF) factor score based on multiple tasks in the UK Biobank (n = 427,037 individuals of European descent).
We found 129 independent genome-wide significant lead variants in 112 distinct loci. cEF was associated with fast synaptic transmission processes (synaptic, potassium channel, and GABA gamma-aminobutyric acid pathways) in gene-based analyses. cEF was genetically correlated with measures of intelligence (IQ) and cognitive processing speed, but cEF and IQ showed differential genetic associations with psychiatric disorders and educational attainment.
Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.
To assess the effectiveness and safety of bimatoprost sustained release (SR) glaucoma implant as a treatment for open-angle glaucoma and ocular hypertension in a real-world private practice setting ...with a significant American Indian population.
This retrospective study included 156 eyes from adult patients who received a single injection of bimatoprost implant between June 2020 and May 2022 at the Oklahoma Eye Surgeons. Patients were stratified by baseline intraocular pressure (IOP) (≥21 mmHg versus IOP<21 mmHg). The co-primary endpoints were changes in the mean IOP and the number of topical IOP-lowering medications from baseline to Month 6.
At 6 months, eyes with baseline IOP≥21 mmHg had a significantly lower mean IOP (19.85±8.01 versus 26.25±4.84 mmHg; p<0.0001) and the mean number of IOP-lowering medications (1.04±1.44 versus 1.38±1.50; p=0.048) compared with baseline. One year after implantation, 73.58% of eyes had a ≥20% reduction in IOP, 41.51% were medication-free and 30.19% were receiving at least one fewer medication. Among eyes with baseline IOP<21 mmHg, there was a significant reduction in the mean number of IOP-lowering medicines by Month 6 (0.61±1.03 versus 1.93±1.21 at baseline; p<0.0001), with no change in IOP. At 12 months, 24.27% of eyes had a ≥20% decrease in IOP, 43.69% of eyes did not require any medications and 63.11% had at least one fewer medication compared with baseline. An analysis using Welch's two-sample
-test showed no significant differences in the outcomes between the overall population and the American Indian population (number of eyes, 23).
Bimatoprost SR glaucoma implant lowered IOP in eyes with high, uncontrolled baseline IOP, while it reduced the number of medications in eyes with a controlled baseline IOP. No clinically meaningful and statistically significant differences in the efficacy of bimatoprost were observed in patients of American Indian descent.
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