Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have ...demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALK
). Functional ALK dependency was confirmed
and
with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy
, synergistic effects were observed upon drug combination.
, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS.
.
•Custom-built 3D weaving machine was used to weave 3D spacer glass fiber fabrics.•PU foaming was directly performed in the vacancies of 3D woven I-beam composites.•Up to 43 % compressive modulus ...increase was obtained via in-situ PU foaming.•Energy absorption was increased in LD-PUFFIC by 173 % under three-point bending.•Post-mortem mechanical test samples were monitored by fractography.
3D weaving of I-beam structures can potentially create delamination- and joint-free structures, expanding their use in engineering applications compared to metal or traditional laminated composite beams. In addition, polymeric foams can be utilized to fill the vacancies between the web and the flanges of I beams, improving the mechanical characteristics and the structural integrity with little to no weight penalty. Moreover, interposing an adhesive layer between the I beam and the foam structure can result in a more effective bonding which intensifies the structure's robustness. In this study, high-performance I-beam composites were produced by combining polymeric foams with 3D woven glass fiber composites. Low- and high-density polyurethane foams were successfully inserted between the web and the flanges of 3D woven glass fiber composites manufactured by the vacuum infusion process using the free-rise foaming method. Samples with adhesive films were also produced to assess and compare their effectiveness with the composites made solely of polyurethane foam and I beam. The increases in energy absorption capacity and compressive and flexural properties were analyzed under compressive and flexural (three-point bending) loading. The obtained results indicate that structural integrity under bending can be substantially improved with the in-situ foaming supported by adhesive layers.
Cancer cells have altered metabolism compared to normal cells, including dependence on glutamine (GLN) for survival, known as GLN addiction. However, some cancer cell lines do not require GLN for ...survival and the basis for this discrepancy is not well understood. GLN is a precursor for antioxidants such as glutathione (GSH) and NADPH, and GLN deprivation is therefore predicted to deplete antioxidants and increase reactive oxygen species (ROS). Using diverse human cancer cell lines we show that this occurs only in cells that rely on GLN for survival. Thus, the preference for GLN as a dominant antioxidant source defines GLN addiction. We show that despite increased glucose uptake, GLN addicted cells do not metabolize glucose via the TCA cycle when GLN is depleted, as revealed by (13)C-glucose labeling. In contrast, GLN independent cells can compensate by diverting glucose-derived pyruvate into the TCA cycle. GLN addicted cells exhibit reduced PDH activity, increased PDK1 expression, and PDK inhibition partially rescues GLN starvation-induced ROS and cell death. Finally, we show that combining GLN starvation with pro-oxidants selectively kills GLN addicted cells. These data highlight a major role for GLN in maintaining redox balance in cancer cells that lack glucose-dependent anaplerosis.
Highlights • We compared the perfusion parameters obtained with both DSC and ASL perfusion imaging methods. • In ASL perfusion imaging, we also created quantitative CBF maps. • All patients included ...in the study had histopathological diagnose. • All MR examinations are done with 3T MR imaging system.
Hypoxic ischemic encephalopathy is one of the main causes of neonatal deaths. The objective of this study was to evaluate the neuroprotective effect of antioxidant and anti-inflammatory properties of ...sodium hydrosulfide (NaHS) in neonatal rats with hypoxic ischemic encephalopathy, as well as its effect on neuronal apoptosis through histopathological and biochemical tests.
Forty-seven-day‑old rats with induced hypoxia‑ischemia (HI) were randomly separated into four groups. Half an hour after the induction of hypoxic-ischemia, serum physiological (SF), 50 µmol/kg NaHS, or 100 µmol/kg NaHS were intraperitoneally given to the rats.
Apoptotic cells in the brain tissue of rats in HI + NaHS 50 μmol/kg, and HI + NaHS 100 μmol/kg groups decreased compared to HI group (p = 0.00). While HI + NaHS 50 μmol/kg and HI + NaHS 100 μmol/kg groups yielded no difference in TNF-α, IL-6, and iNOS levels as compared to the HI group, an increase in NGF was detected in the 50 µmol/kg and 100 µmol/kg NaHS groups (p = 0.34, p = 0.24, p = 0.26, p = 0.026, p = 0.017). When TOS, TAS and OSI levels were compared, an increase in TAS and OSI and a decrease in TOS were observed in the treatment groups as compared to HI group.
NaHS given to hypoxic-ischemic encephalopathy model significantly decreased apoptosis in neurons and had a neuroprotective efficacy with an increase in NGF levels (Tab. 1, Fig. 3, Ref. 25).
A Citrobacter strain (WYE1) was isolated from a UK soil by enrichment using the glucosinolate sinigrin as sole carbon source. The enzyme myrosinase was purified using a combination of ion exchange ...and gel filtration to give a pure protein of approximately 66 kDa. The N-terminal amino acid and internal peptide sequence of the purified protein were determined and used to identify the gene, which, based on InterPro sequence analysis, belongs to the family GH3, contains a signal peptide, and is a periplasmic protein with a predicted molecular mass of 71.8 kDa. A preliminary characterization was carried out using protein extracts from cell-free preparations. The apparent K M and V max were 0.46 mM and 4.91 mmol dm–3 min–1 mg–1, respectively, with sinigrin as substrate. The optimum temperature and pH for enzyme activity were 25 °C and 6.0, respectively. The enzyme was marginally activated with ascorbate by a factor of 1.67.
Objectives
Frailty is a state of homeostenosis associated with adverse outcomes. Chronic kidney disease (CKD) increases considerably by aging and shares the common risk factors with frailty. We aimed ...to examine the prevalence and independent associates of frailty status in CKD patients.
Design
In this single-centre, cross-sectional study, we used the five-item Fatigue, Resistance, Ambulation, Illnesses and Loss of Weight (FRAIL) scale to evaluate frailty. A binary logistic regression analysis model including the parameters found to have relationship with frailty in univariate analyses was used to detect independent associates of frailty status. Odds ratio (OR) and 95% confidence interval (CI) were given.
Participants
Study included 148 patients aged 18–80. Sixty (60) patients were end stage renal disease (ESRD) patients on maintenance hemodialysis (HD) (at least for 3 months) and 88 were stage 3–4 CKD patients. Thirty-seven (
37
) patients (42%) were eGFR G3a, 31 patients (35.3%) were eGFR G3b and 20 patients (22.7%) were eGFR G4 in stage 3–4 CKD patients.
Measurements
Demographics, etiology of CKD, comorbidities, regular drugs, dialysis-related and laboratory data were recorded. FRAIL scale was scored as follows; 0=robust, 1–2=prefrail, and ≥3=frail. The frailty status was compared between frail+prefrail group vs robust (non-frail) group.
Results
The prevalences of prefrailty and frailty were 68.3% and 3.3% in HD group and 53.4% and zero in stage 3–4 CKD group, respectively (p = 0.025). In the multivariate logistic regression analysis, being in HD group (OR=3.87, 95% CI= 1.06–14.19, p=0.04), older age (OR=1.09, 95% CI= 1.04–1.13) and female sex (OR=9.13, 95% CI= 2.82–29.46) were independent risk factors for frailty (p<0.001, for both).
Conclusion
Prefrailty and frailty are quite common among HD and CKD stage 3–4 patients. Being an HD patient is an independent risk factor for non-robust (frail or prefrail) status. Our findings point out a remarkably high prevalence of frailty severity (prefrailty/frailty) phenotype among patients with advanced CKD stages.
Vitamin D has beneficial effects, some of which involve the cardiovascular system. No study to date has investigated the association between serum endocan levels, as a biomarker of endothelial ...inflammation, and vitamin D levels in the absence of subclinical atherosclerosis detected by carotid intima-media thickness (CIMT) in healthy individuals.
Subjects were categorized into three groups based on vitamin D levels according to Endocrine Society guidelines. Mean CIMT was calculated from six measurements on two scans. Statistical significance was set at p < 0.05, and all testing was two-sided.
The concentration of serum endocan was 802.8 ± 411.4 ng/L in the group with the lowest serum vitamin D level, 454.8 ± 334.3 ng/L in the mild/moderately low serum vitamin D level group, and 269.4 ± 180.2 ng/L in the group with normal serum vitamin D levels (p < 0.01). Receiver operating characteristics curve analysis revealed that a serum vitamin D concentration of 7.5 ng/mL had a 97% sensitivity and 81% specificity for the prediction of serum endocan level greater than 270 ng/L, which could be an indicator for endothelial inflammation.
Demonstrating that vitamin D deficiency can cause endothelial damage in the early period of atherosclerosis without the development of clinical cardiovascular disease will have a pivotal role in the prevention of cardiovascular mortality and morbidity.
Purpose
Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in
ACP5.
We aimed to provide a survey of the skeletal, neurological and immune manifestations of ...this disease in a cohort of molecularly confirmed cases.
Methods
We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic
ACP5
mutations.
Results
We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.
Conclusions
Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.
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