Proteomic Profiling of Small Extracellular Vesicles Isolated from the Plasma of Vietnamese Patients with Non-Small Cell Lung Cancer Reveals Some Potential Biomarkers

Background: Considering the poor prognosis of non-small cell lung cancer (NSCLC), the objective of this study was to examine the potential of plasma-derived vesicles as a source of lung cancer-specific proteins. Extracellular vesicle (EV) cargos are specific to the source cells, hence they have the potential of being a source of cancer-specific proteins.  Methods: The proteins differently expressed in cancer were determined and derived from EVs isolated from the plasma of NSCLC patients at the National Lung Hospital. To this end, purification was done using gel filtration chromatography and ultracentrifugation. In addition, nano liquid chromatography mass spectrometry (LC–MS/MS) was used for analyzing. Results: Fifty-seven EV-derived proteins related to NSCLC were highlighted in this research. Some of them have not been addressed before, such as EEF1A1 (elongation factor 1-α1), KPNB1 (Importin subunit beta 1), SRC (proto-oncogene tyrosine-protein kinase) and ACTC1 (actin, alpha cardiac muscle 1). This list was further confirmed through a comparison with ExoCarta and Vesiclepedia. Conclusion: This study is the first work to show the involvement of several novel proteins of small EV (EEF1A1, KPNB1, SRC, and ACTC1) in the progression of NSCLC. The results suggested that they could serve as novel biomarkers for non-small cell lung cancer in the future.     

Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism

We investigated whether protein kinase C (PKC) is involved in trimethyltin (TMT)-induced neurotoxicity. TMT treatment (2.8 mg/kg, i.p.) significantly increased PKCδ expression out of PKC isozymes (i.e., α, βI, βII, δ, and ?) in the hippocampus of wild-type (WT) mice. Consistently, treatment with TMT resulted in significant increases in cleaved PKCδ expression. Genetic or pharmacological inhibition (PKCδ knockout or rottlerin) was less susceptible to TMT-induced seizures than WT mice. TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species. These effects were more pronounced in the WT mice than in PKCδ knockout mice. In addition, the ability of TMT to induce nuclear translocation of Nrf2, Nrf2 DNA-binding activity, and upregulation of γ-glutamylcysteine ligase was significantly increased in the PKCδ knockout mice and rottlerin (10 or 20 mg/kg, p.o. × 6)-treated WT mice. Furthermore, neuronal degeneration (as shown by nuclear chromatin clumping and TUNEL staining) in WT mice was most pronounced 2 days after TMT. At the same time, TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling was evident, thereby decreasing phospho-Bad, expression of Bcl-xL and Bcl-2, and the interaction between phospho-Bad and 14-3-3 protein, and increasing Bax expression and caspase-3 cleavage were observed. Rottlerin or PKCδ knockout significantly protected these changes in anti- and pro-apoptotic factors. Importantly, treatment of the PI3K inhibitor LY294002 (0.8 or 1.6 µg, i.c.v.) 4 h before TMT counteracted protective effects (i.e., Nrf-2-dependent glutathione induction and pro-survival phenomenon) of rottlerin. Therefore, our results suggest that down-regulation of PKCδ and up-regulations of Nrf2-dependent glutathione defense mechanism and PI3K/Akt signaling are critical for attenuating TMT neurotoxicity.     

Importance of Albumin, 25(OH)-Vitamin D and IGFBP-3 as Risk Factors in Elderly Women and Men with Hip Fracture

The relative importance of vitamin D deficiency, secondary hyperparathyroidism, nutritional deficiency and low bone mineral density (BMD) as risk factors for hip fracture is not definitely established. In the framework of a case-control study of risk factors for hip fractured, biochemical markers of bone metabolism and nutrition and femoral BMD data were compared in 136 female and 43 male hip fracture patients, 126 female and 44 male age-matched hospitalized controls, and 47 healthy elderly women (8 men). Patients with hip fracture had lower albumin (−10%9 and 25(OH)-vitamin D (25(OH)D; −19%) compared with hospitalized controls, and lower albumin (−28%) and 25(OH)D levels (−52%) compared with the elderly controls. Serum values of IGFBP-3 were also significantly lower (−33%) in hip fracture patients than in community controls. BMD of femoral neck was lower (p < 0.001) in patients than in hospitalized and community controls. In hip fracture patients, parathyroid hormone (PTH) correlated weakly with BMD (neck: r = −0.19, trochanter: r = −0.17; both p < 0.05). When all women were pooled (n = 233), albumin correlated significantly (age-adjusted) with BMD at all sites (neck: r = 0.27, trochanter: r = 0.25; all p < 0.001). Albumin, but not 25(OH)D, also correlated with skinfold thickness (r = 0.19, p < 0.0025) and with body mass index (BMI) (r = 0.14, p < 0.05). Male patients with hip fracture had lower BMD and albumin (both p < 0.001), 25(OH)D (p = 0.02) and IGFBP-3 levels (p <: 0.005) compared with the controls. When male patients and controls were pooled together, albumin, skinfold thickness and BMI were significantly correlated with each other, but not with BMD. IGFBP-3 was highly correlated with albumin (p < 0.0001), 25(OH)D (p < 0.005) and, less significantly, with PTH (p < 0.05), but not with BMI or skinfold thickness. IGFBP-3 was significantly correlated with BMD at all sites (neck: r = 0.27, p < 0.05); trochanter: r = 0.40, p < 0.0005). In conclusion, low albumin and low BMD were both important risk factors for hip fracture. Low serum albumin was the strongest independent variable correlated with hip fractures. In men, IGFBP-3 was correlated with BMD. The femoral BMD depended only weakly on PTH and 25(OH)D, but was correlated at all sites with albumin, a non-specific parameter of nutrition and general health.     

Modulation of calcium-activated chloride current via pH-induced changes of calcium channel properties in cone photoreceptors.

The activity of calcium-activated chloride channels is controlled through the complex interaction of cellular mechanisms affecting calcium entry, buffering, and extrusion, and an unknown stoichiometric relation between intracellular Ca concentration and Cl channel activation. Here, we show that calcium-activated chloride current [ICl(Ca)] in cone photoreceptors is also highly sensitive to external pH, being strongly reduced by acidification and enhanced by alkylinization of the bathing medium. We propose that this modulation is accounted for by the pH sensitivity of Ca channel activation and permeation, already well characterized in other cells, which we now extend to cone photoreceptor Ca channels. Acidification of the external medium from a control pH of 7.4 shifts the Ca channel activation range positively by about 10 mV at pH 6.8, reducing the magnitude of calcium current with a consequent reduction of chloride current. Alkylinization shifts the Ca channel activation range negatively by about 8 mV at pH 8 and produces larger calcium currents during step depolarizations that in turn elicit larger chloride tail currents. Modulation of ICl(Ca) by pH suggests other consequences of the pH-induced shift in Ca channel gating, for one, modification of Ca-dependent transmitter release, which could be especially significant in photoreceptors where the cell's operating voltage range overlaps only the lower end of the Ca channel activation range.     

Magnetic resonance angiography (MRA) of the circle of Willis: a prospective comparison with conventional angiography in 54 subjects

We prospectively correlated the findings of magnetic resonance angiography (MRA) with those of transfemoral four-vessel angiography in 54 patients to investigate the direction of flow within the circle of Willis. Our primary goal was to assess the direction of flow using the size of the vessel and signal intensity, without saturation techniques. Analysis of the circle of Willis, especially the communicating arteries, was performed double-blind by two groups of two radiologists. Three types of arteries were identified: high flow or cross-cerebral circulation, patent and nonvisualised arteries. Cerebral angiography was the standard for comparison between the two methods. MRA did not reveal any arteries invisible on angiography, thus providing a specificity of 100%. The sensitivity of MRA was 89.2% for the anterior and 81.3% for the posterior communicating arteries, and 100% for the anterior, middle and posterior cerebral arteries. MRA was shown to be a useful technique for the assessment of patency of the circle of Willis.     

Modulation of high-dose methotrexate toxicity by a non-toxic level of 5-fluorouracil

High-dose methotrexate (MTX) toxicity is reduced by a non-toxic dose of 5-fluorouracil (FU) when these agents are used in combination. Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, hemoglobin, and hematocrit), ileal tissue, body weight, and mean survival were used as parameters to assess toxicity. For all parameters studied, there were no significant differences between the scheduling of MTX (245 mg/kg) after a priming dose of FU (25 mg/kg), simultaneous MTX and FU, FU alone, and control. However, sequential treatment with MTX followed by FU, and MTX alone resulted in: a marked decrease in the hematopoietic parameters; significant morphological changes in ileal tissue; a reduction of body weight; and increased mortality of animals. Hence, this study suggests that FU, a cytotoxic agent, may protect against MTX toxicity and improve its therapeutic index when FU administration precedes MTX or when these agents are given simultaneously.     

Congenital absence of the inferior rectus muscle--diagnosis and management.

BACKGROUND: Congenital absence of the inferior rectus muscle is a rare cause of apparent inferior rectus palsy especially in the absence of associated cranial facial anomalies. METHODS: We report three cases of isolated congenital absence of the inferior rectus muscle and its successful surgical management. RESULTS: Failure of the normal embryologic development of the mesodermal complex around the eye can lead to agenesis of the extraocular muscles. In apparent palsies of the inferior rectus muscle and no definite cause, a high index of suspicion and orbital imaging can confirm the diagnosis of congenitally absent inferior rectus preoperatively. Surgical correction may involve inferior transposition of the horizontal rectus muscles. CONCLUSIONS: Although rare, congenital absence of the inferior rectus muscle is a possible cause of apparent inferior rectus muscle palsy particularly in the absence of another identifiable cause. Strabismus surgery in conjunction with intramuscular botulinum toxin injection can offer significant improvement in function and cosmesis of these patients.