Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and ...neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.
Purpose: To establish the frequency of IDH1 mutations in glioblastomas at a population level, and to assess whether they allow reliable discrimination between primary
( de novo ) glioblastomas and ...secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma.
Experimental Design: We screened glioblastomas from a population-based study for IDH1 mutations and correlated them with clinical data and other genetic alterations.
Results: IDH1 mutations were detected in 36 of 407 glioblastomas (8.8%). Glioblastoma patients with IDH1 mutations were younger (mean, 47.9 years) than those with EGFR amplification (60.9 years) and were associated with significantly longer survival (mean, 27.1 versus 11.3 months; P < 0.0001). IDH1 mutations were frequent in glioblastomas diagnosed as secondary (22 of 30; 73%), but rare in primary glioblastomas (14 of
377; 3.7%: P < 0.0001). IDH1 mutations as genetic marker of secondary glioblastoma corresponded to the respective clinical diagnosis in 95% of cases.
Glioblastomas with IDH1 mutation diagnosed as primary had clinical and genetic profiles similar to those of secondary glioblastomas, suggesting that
they may have rapidly progressed from a less malignant precursor lesion that escaped clinical diagnosis and were thus misclassified
as primary. Conversely, glioblastomas without IDH1 mutations clinically diagnosed as secondary typically developed from anaplastic rather than low-grade gliomas, suggesting
that at least some were actually primary glioblastomas, that may have been misclassified, possibly due to histologic sampling
error.
Conclusion: IDH1 mutations are a strong predictor of a more favorable prognosis and a highly selective molecular marker of secondary glioblastomas
that complements clinical criteria for distinguishing them from primary glioblastomas. (Clin Cancer Res 2009;15(19):6002â7)
IDH1 encodes isocitrate dehydrogenase 1, which participates in the citric acid cycle and was recently reported to be mutated in 12% of glioblastomas. We assessed IDH1 mutations in 321 gliomas of ...various histological types and biological behaviors. A total of 130 IDH1 mutations was detected, and all were located at amino acid residue 132. Of these, 91% were G→A mutations (Arg→His). IDH1 mutations were frequent in low-grade diffuse astrocytomas (88%) and in secondary glioblastomas that developed through progression from low-grade diffuse or anaplastic astrocytoma (82%). Similarly, high frequencies of IDH1 mutations were found in oligodendrogliomas (79%) and oligoastrocytomas (94%). Analyses of multiple biopsies from the same patient (51 cases) showed that there were no cases in which an IDH1 mutation occurred after the acquisition of either a TP53 mutation or loss of 1p/19q, suggesting that IDH1 mutations are very early events in gliomagenesis and may affect a common glial precursor cell population. IDH1 mutations were co-present with TP53 mutations in 63% of low-grade diffuse astrocytomas and with loss of heterozygosity 1p/19q in 64% of oligodendrogliomas; they were rare in pilocytic astrocytomas (10%) and primary glioblastomas (5%) and absent in ependymomas. The frequent presence of IDH1 mutations in secondary glioblastomas and their near-complete absence in primary glioblastomas reinforce the concept that despite their histological similarities, these subtypes are genetically and clinically distinct entities.
Underarm throwing motions are crucial in various sports, including boccia. Unlike healthy players, people with profound weakness, spasticity, athetosis, or deformity in the upper limbs may struggle ...or find it difficult to control their hands to hold or release a ball using their fingers at the proper timing. To help them, our study aims to understand underarm throwing motions. We start by defining the throwing intention in terms of the launch angle of a ball, which goes hand-in-hand with the timing for releasing the ball. Then, an appropriate part of the body is determined in order to estimate ball-throwing intention based on the swinging motion. Furthermore, the geometric relationship between the movements of the body part and the release angle is investigated by involving multiple subjects. Based on the confirmed correlation, a calibration-and-estimation model that considers individual differences is proposed. The proposed model consists of calibration and estimation modules. To begin, as the calibration module is performed, individual prediction states for each subject are updated online. Then, in the estimation module, the throwing intention is estimated employing the updated prediction. To verify the effectiveness of the model, extensive experiments were conducted with seven subjects. In detail, two evaluation directions were set: (1) how many balls need to be thrown in advance to achieve sufficient accuracy; and (2) whether the model can reach sufficient accuracy despite individual differences. From the evaluation tests, by throwing 20 balls in advance, the model could account for individual differences in the throwing estimation. Consequently, the effectiveness of the model was confirmed when focusing on the movements of the shoulder in the human body during underarm throwing. In the near future, we expect the model to expand the means of supporting disabled people with ball-throwing disabilities.
Kisspeptin-10 (KP-10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention with respect to atherosclerosis, since both KP-10 and ...GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury. The present review introduces the emerging roles of the KP-10/GPR54 system in atherosclerosis.
KP-10 suppresses migration and proliferation of human umbilical vein endothelial cells (HUVECs), and induces senescence in HUVECs. KP-10 increases adhesion of human monocytes to HUVECs. KP-10 also stimulates expression of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin genes in HUVECs. KP-10 enhances oxidized low-density lipoprotein-induced foam cell formation associated with upregulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, KP-10 suppresses angiotensin II-induced migration and proliferation, however, it enhances apoptosis and activities of matrix metalloproteinase (MMP)-2 and MMP-9 by upregulation of extracellular signal-regulated kinase 1/2, p38, Bax, and caspase-3. Four-week-infusion of KP-10 into Apoe−/- mice accelerates development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation, also, it decreases intraplaque vascular smooth muscle cell content. Proatherosclerotic effects of endogenous and exogenous KP-10 were completely attenuated upon infusion of P234, a GPR54 antagonist, in Apoe−/− mice.
These findings suggest that KP-10 may contribute to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques. This GPR54 antagonist may be useful for the prevention and treatment of atherosclerosis. Thus, the KP-10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.
•A potent vasoconstrictor kisspeptin-10 (KP-10) and its receptor GPR54 have currently received much attention with respect to atherosclerosis.•Both KP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury.•KP-10 contributes to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques.•GPR54 antagonists are useful for the prevention and treatment of atherosclerosis.•The KP-10/GPR54 system may serve as a promising biomarker and therapeutic target for atherosclerotic diseases.
The blood-brain barrier (BBB) is formed by brain endothelial cells. Many immortalized brain endothelial cell lines have been established; these have been used as in vitro BBB models. The aim of the ...present study was to assess the paracellular barrier properties of the immortalized mouse brain endothelial cell lines bEND.3, bEND.5 cells, and mouse brain endothelial cell 4 (MBEC4), and those of the primary mouse brain endothelial cells pMBECs. bEND.3 cells showed low permeability to sodium fluorescein and obvious staining of tight junction proteins (claudin-5, occludin and ZO-1) similar to pMBECs; these barrier properties of MBEC4 and bEND.5 cells were low. In addition, bEND.3 cells expressed the highest level of claudin-5 among all cells. These results suggest that bEND.3 cells are a convenient and useful model for evaluating BBB function, especially the paracellular barrier.
Omentin-1, a novel adipocytokine expressed in visceral fat tissue, is negatively correlated with obesity, insulin resistance, and stable coronary artery disease (CAD). However, there have been no ...previous reports regarding the effects of omentin-1 on atherogenesis.
This study was performed to evaluate the atheroprotective effects of omentin-1 on human monocyte-derived macrophages, human aortic smooth muscle cells (HASMCs) in vitro, and aortic lesions in Apoe(-/-) mice in vivo. The histological expression of omentin-1 in coronary artery lesions and epicardial adipose tissues and its plasma levels were compared between CAD and non-CAD patients. Omentin-1 was abundantly expressed in human umbilical vein endothelial cells, macrophages, HASMCs, and human coronary artery SMCs in vitro. Omentin-1 promoted anti-inflammatory M2 phenotype during differentiation of human monocytes into macrophages. Omentin-1 suppressed oxidized low-density lipoprotein-induced foam cell formation associated with down-regulation of CD36, scavenger receptor class A, and acyl-CoA:cholesterol acyltransferase-1 and up-regulation of neutral cholesterol ester hydrolase in human macrophages. Omentin-1 suppressed angiotensin II-induced migration and platelet-derived growth factor-BB-induced proliferation, and collagen-1 and -3 expression in HASMCs. Four-week infusion of omentin-1 into Apoe(-/-) mice retarded the development of aortic atherosclerotic lesions with reduced contents of monocytes/macrophages, SMCs, and collagen fibres along with peritoneal M2-activated macrophages with inflammasome down-regulation and lowered plasma total cholesterol levels. Omentin-1 levels were markedly reduced in coronary endothelium and epicardial fat but increased in plasma and atheromatous plaques (macrophages/SMCs) in CAD patients compared with non-CAD patients.
This study provided the first evidence that omentin-1 may serve as a novel therapeutic target for atherosclerosis and CAD.
Myasthenic crisis, a life-threatening exacerbation of myasthenia gravis, is a significant clinical challenge, particularly when refractory to standard therapies. Here, we described a case of ...myasthenic crisis in which the patient transitioned from refractory myasthenic crisis to minimal symptom expression after receiving add-on treatment with efgartigimod, a novel neonatal Fc receptor antagonist. A 54 years-old woman who was diagnosed with anti-acetylcholine receptor antibody-positive myasthenia gravis experienced respiratory failure necessitating mechanical ventilation. Despite aggressive treatment with plasmapheresis, intravenous immunoglobulins, and high-dose corticosteroids, her condition continued to deteriorate, culminating in persistent myasthenic crisis. Efgartigimod was administered as salvage therapy. Remarkable improvement in neuromuscular function was observed within days, allowing for successful weaning from mechanical ventilation. Over the subsequent weeks, the patient's symptoms continued to ameliorate, ultimately reaching a state of minimal symptom expression. Serial assessments of her serum anti-acetylcholine receptor antibody titer showed a consistent decline in parallel with this clinical improvement. This case highlights efgartigimod's potential as an effective therapeutic option for refractory myasthenic crisis, offering new hope for patients facing this life-threatening condition.
Adropin, a peptide hormone expressed in liver and brain, is known to improve insulin resistance and endothelial dysfunction. Serum levels of adropin are negatively associated with the severity of ...coronary artery disease. However, it remains unknown whether adropin could modulate atherogenesis. We assessed the effects of adropin on inflammatory molecule expression and human THP1 monocyte adhesion in human umbilical vein endothelial cells (HUVECs), foam cell formation in THP1 monocyte-derived macrophages, and the migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro and atherogenesis in
mice in vivo. Adropin was expressed in THP1 monocytes, their derived macrophages, HASMCs, and HUVECs. Adropin suppressed tumor necrosis factor α-induced THP1 monocyte adhesion to HUVECs, which was associated with vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 downregulation in HUVECs. Adropin shifted the phenotype to anti-inflammatory M2 rather than pro-inflammatory M1 via peroxisome proliferator-activated receptor γ upregulation during monocyte differentiation into macrophages. Adropin had no significant effects on oxidized low-density lipoprotein-induced foam cell formation in macrophages. In HASMCs, adropin suppressed the migration and proliferation without inducing apoptosis via ERK1/2 and Bax downregulation and phosphoinositide 3-kinase/Akt/Bcl2 upregulation. Chronic administration of adropin to
mice attenuated the development of atherosclerotic lesions in the aorta, with reduced the intra-plaque monocyte/macrophage infiltration and smooth muscle cell content. Thus, adropin could serve as a novel therapeutic target in atherosclerosis and related diseases.
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