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The presence of complex N-glycans with β1,6-N-acetylglucosamine (GlcNAc) on cells has long been associated with cancer. For this reason, the role of N-acetylglucosaminyltransferase-III (GnT-III, MGAT3) to hinder terminal N-glycan processing by the addition of β1,4-GlcNAc residues (bisected N-glycan), has earned GnT-III a reputation as a tumor suppressor. In this study, by the creation and characterization of human MGAT3 knockout in the Be(2)-C cell line, a NB cell line, (MGAT3-/-), we solidify GnT-III activity as a suppressor of NB progression by showing that the loss of GnT-III coincided with increased cell proliferation and cell spheroid invasion, along with cell migration, and cell-cell adhesion, and modified cell types. Lectin blotting results indicated that bisected N-glycans were greatly diminished in MGAT3-/-. Further GNL and L-PHA binding suggested that oligomannose and β1,6-GlcNAc branched N-glycans were raised in MGAT3-/- relative to the BE(2)-C cell line. Cellular phenotypes of MGAT3-/- could be rescued by transient expression of Mgat3 cDNA. Likewise, altered levels of bisecting GlcNAc N-glycans in a rat NB cell line (NB_1) overexpressing GnT-III had reduced cell-cell adhesion, cell migration, and cell invasiveness. We conclude that lowered GnT-III activity promotes cell invasiveness and growth in NB, and speculate that oligomannose and β1,6-GlcNAc branched N-glycans are key determinants.

Tumor development can be promoted/suppressed by certain N-glycans attached to proteins at the cell surface. Here we examined aberrant neuronal properties in 2D and 3D rat neuroblastoma (NB) cell cultures with different N-glycan populations. Lectin binding studies revealed that the engineered N-glycosylation mutant cell line, NB_1(- Mgat1 ), expressed solely oligomannose N-glycans, and verified that the parental cell line, NB_1, and a previous engineered N-glycosylation mutant, NB_1(- Mgat2 ), expressed significant levels of higher order N-glycans, complex and hybrid N-glycans, respectively. NB_1 grew faster than mutant cell lines in monolayer and spheroid cell cultures. A 2-fold difference in growth between NB_1 and mutants occurred much sooner in 2D cultures relative to that observed in 3D cultures. Neurites and spheroid cell sizes were reduced in mutant NB cells of 2D and 3D cultures, respectively. Cell invasiveness was highest in 2D cultures of NB_1 cells compared to that of NB_1(- Mgat1 ). In contrast, NB_1 spheroid cells were much less invasive relative to NB_1(- Mgat1 ) spheroid cells while they were more invasive than NB_1(- Mgat2 ). Gelatinase activities supported the ranking of cell invasiveness in various cell lines. Both palladin and HK2 were more abundant in 3D than 2D cultures. Levels of palladin, vimentin and EGFR were modified in a different manner under 2D and 3D cultures. Thus, our results support variations in the N-glycosylation pathway and in cell culturing to more resemble in vivo tumor environments can impact the aberrant cellular properties, particularly cell invasiveness, of NB.

Physical activity is an important nonpharmacological strategy for managing arthritis-attributable pain and improving physical function. To prepare health care providers (HCPs) to deliver this care, the National Association of Chronic Disease Directors, the Centers for Disease Control and Prevention, and Medscape Education developed an online clinical practice assessment activity (CPA). This activity aimed to help HCPs assess their knowledge of arthritis-appropriate, evidence-based interventions (AAEBIs) and better incorporate them into treatment programs. A 27-question CPA was launched in November 2022 and analyzed in May 2025. Educational effectiveness was assessed with a repeated-pairs preassessment/postassessment. Responses to multiple choice and confidence questions were aggregated and analyzed to help us understand participants' current practices and education needs for the management of patients with arthritis. Approximately 20,000 HCPs accessed the CPA; 4,395 completed the assessment and were included in the analysis. Less than two-thirds (59.8%) correctly identified recommendations about weekly moderate-intensity physical activity for adults with arthritis. After participating in the CPA, 82.2% agreed or strongly agreed that their awareness of AAEBIs and their benefits had increased. HCPs showed a need for education to reinforce, improve, or extend knowledge about arthritis risk factors, barriers to physical activity, and physical activity prescription.

Tumor development can be promoted/suppressed by certain N-glycans attached to proteins at the cell surface. Here we examined aberrant neuronal properties in 2D and 3D rat neuroblastoma (NB) cell cultures with different N-glycan populations. Lectin binding studies revealed that the engineered N-glycosylation mutant cell line, NB₁(-Mgat1), expressed solely oligomannose N-glycans, and verified that the parental cell line, NB₁, and a previous engineered N-glycosylation mutant, NB₁(-Mgat2), expressed significant levels of higher order N-glycans, complex and hybrid N-glycans, respectively. NB₁ grew faster than mutant cell lines in monolayer and spheroid cell cultures. A 2-fold difference in growth between NB₁ and mutants occurred much sooner in 2D cultures relative to that observed in 3D cultures. Neurites and spheroid cell sizes were reduced in mutant NB cells of 2D and 3D cultures, respectively. Cell invasiveness was highest in 2D cultures of NB₁ cells compared to that of NB₁(-Mgat1). In contrast, NB₁ spheroid cells were much less invasive relative to NB₁(-Mgat1) spheroid cells while they were more invasive than NB₁(-Mgat2). Gelatinase activities supported the ranking of cell invasiveness in various cell lines. Both palladin and HK2 were more abundant in 3D than 2D cultures. Levels of palladin, vimentin and EGFR were modified in a different manner under 2D and 3D cultures. Thus, our results support variations in the N-glycosylation pathway and in cell culturing to more resemble in vivo tumor environments can impact the aberrant cellular properties, particularly cell invasiveness, of NB.

Aberrant N-glycosylation has been associated with progression of the pediatric cancer neuroblastoma (NB) but remains understudied. Here we investigated oligomannose N-glycans in NB by genetic editing of MGAT1 in a human NB cell line, BE(2)-C, called BE(2)-C(MGAT1−/−). Lectin binding studies confirmed that BE(2)-C(MGAT1−/−) had decreased complex and increased oligomannose N-glycans. The relevance of 2D and 3D cell cultures was demonstrated for cell morphology, cell proliferation, and cell invasion, thereby highlighting the necessity for 3D cell culture in investigating cancerous properties. Western blotting revealed that oligomannosylated EGFR had increased autophosphorylation. Proliferation was decreased in BE(2)-C(MGAT1−/−) using 2D and 3D cultures, but both cell lines had similar proliferation rates using 3D cultures without serum. Upon EGF treatment, BE(2)-C(MGAT1−/−), but not BE(2)-C, showed increased proliferation, and furthermore, the mutant proliferated much faster than BE(2)-C under 3D conditions. Cell spheroid invasiveness was greatly increased in BE(2)-C(MGAT1−/−) compared with BE(2)-C. Moreover, invasiveness was reduced in both cell lines with either EGF or RhoA activator treatment, regardless of the N-glycan population. Thus, this study further extends our earlier findings that oligomannose N-glycans enhance NB cell invasiveness, and that EGF stimulation of oligomannosylated EGFR greatly enhances cell proliferation rates, underlining the role of oligomannose N-glycans in the promotion of NB.

Enhanced N-glycan branching is associated with cancer, but recent investigations supported the involvement of less processed N-glycans. Herein, we investigated how changes in N-glycosylation influence cellular properties in neuroblastoma (NB) using rat N-glycan mutant cell lines, NB_1(-Mgat1), NB_1(-Mgat2) and NB_1(-Mgat3), as well as the parental cell line NB_1. The two earlier mutant cells have compromised N-acetylglucosaminyltransferase-I (GnT-I) and GnT-II activities. Lectin blotting showed that NB_1(-Mgat3) cells had decreased activity of GnT-III compared to NB_1. ESI-MS profiles identified N-glycan structures in NB cells, supporting genetic edits. NB_1(-Mgat1) had the most oligomannose N-glycans and the greatest cell invasiveness, while NB_1(-Mgat2) had the fewest and least cell invasiveness. The proliferation rate of NB_1 was slightly slower than NB_1(-Mgat3), but faster than NB_1(-Mgat1) and NB_1(-Mgat2). Faster proliferation rates were due to the faster progression of those cells through the G1 phase of the cell cycle. Further higher levels of oligomannose with 6–9 Man residues indicated faster proliferating cells. Human NB cells with higher oligomannose N-glycans were more invasive and had slower proliferation rates. Both rat and human NB cells revealed modified levels of ER chaperones. Thus, our results support a role of oligomannose N-glycans in NB progression; furthermore, perturbations in the N-glycosylation pathway can impact chaperone systems.

In preparation for a possible large epidemiological study of radiation-related leukemia in Chernobyl clean-up workers of Ukraine, histologic evaluation of 62 cases of leukemia and related disorders was conducted by a panel of expert hematologists and hematopathologists from the United States, France, and Ukraine. All cases were randomly selected from a surrogate population of men in the general population of 6 regions of Ukraine who were between the ages of 20 and 60 years in 1986 and were reported to have developed leukemia, myelodysplasia, or multiple myeloma between the years 1987 and 1998. The hematologists and hematopathologists on the panel were in agreement with one another and with the previously reported diagnoses and classifications of about 90% of the cases of acute and chronic leukemia in the study. These results suggest that strong reliance can be placed on the clinical diagnoses of acute and chronic forms of leukemia and multiple myeloma that have occurred in Ukrainian Chernobyl clean-up workers providing that the diagnoses are supported by records of the patients having had adequate histologic bone marrow studies. The number of cases in this study with the diagnosis of myelodysplasia, however, was too small to draw firm conclusions.

Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting, and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. The Hypertension in the Very Elderly trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function. Patients with hypertension (systolic pressure 160–200 mm Hg; diastolic pressure <110 mm Hg) who were aged 80 years or older were enrolled in this double-blind, placebo-controlled trial. Participants were randomly assigned to receive 1·5 mg slow release indapamide, with the option of 2–4 mg perindopril, or placebo. The target systolic blood pressure was 150 mm Hg; the target diastolic blood pressure was 80 mm Hg. Participants had no clinical diagnosis of dementia at baseline, and cognitive function was assessed at baseline and annually with the mini-mental state examination (MMSE). Possible cases of incident dementia (a fall in the MMSE score to <24 points or a drop of three points in 1 year) were assessed by standard diagnostic criteria and expert review. The trial was stopped in 2007 at the second interim analysis after treatment resulted in a reduction in stroke and total mortality. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00122811. 3336 HYVET participants had at least one follow-up assessment (mean 2·2 years) and were included: 1687 participants were randomly assigned to the treatment group and 1649 to the placebo group. Only five reports of adverse effects were attributed to the medication: three in the placebo group and two in the treatment group. The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic −15 mm Hg, p<0·0001; and diastolic −5·9 mm Hg, p<0·0001. There were 263 incident cases of dementia. The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group. There was no significant difference between treatment and placebo groups (hazard ratio [HR] 0·86, 95% CI 0·67–1·09); however, when these data were combined in a meta-analysis with other placebo-controlled trials of antihypertensive treatment, the combined risk ratio favoured treatment (HR 0·87, 0·76–1·00, p=0·045). Antihypertensive treatment in elderly patients does not statistically reduce incidence of dementia. This negative finding might have been due to the short follow-up, owing to the early termination of the trial, or the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis, might support antihypertensive treatment to reduce incident dementia. The British Heart Foundation; the Institute de Recherches Internationales Servier.

Background: Postural strategies such as ankle, hip, or combined ankle-hip strategies are used to maintain optimal postural stability, which can be influenced by the footwear type and physiological workload. Purpose: This paper reports previously unreported postural strategy scores during the six conditions of the sensory organization test (SOT). Methods: Fourteen healthy males (age: 23.6 ± 1.2 years; height: 181 ± 5.3 cm; mass: 89.2 ± 14.6 kg) were tested for postural strategy adopted during SOT in three types of occupational footwear (steel-toed work boot, tactical work boot, low-top work shoe) every 30 min during a 4-h simulated occupational workload. Postural strategy scores were analyzed using repeated measures analysis of variance at 0.05 alpha level. Results: Significant differences among postural strategy scores were only evident between SOT conditions, and but not between footwear type or the workload. Conclusions: Findings indicate that occupational footwear and occupational workload did not cause a significant change in reliance on postural strategies. The significant changes in postural strategy scores were due to the availability of accurate and/or conflicting sensory feedback during SOT conditions. In SOT conditions where all three types of sensory feedback was available, the ankle strategy was predominantly adopted, while more reliance on hip strategy occurred in conditions with absent or conflicting sensory feedback.