Soluble LR11 as a Novel Biomarker in Acute Kawasaki Disease.

BACKGROUND: Intimal smooth muscle cells (SMCs) play an important role in the vasculitis caused by Kawasaki disease (KD). Lipoprotein receptor 11 (LR11) is a member of the low-density lipoprotein receptor family, which is expressed markedly in intimal vascular SMCs and secreted in a soluble form (sLR11). sLR11 has been recently identified as a potential vascular lesion biomarker. sLR11 is reportedly elevated in patients with coronary artery lesions long after KD, but there is no description of sLR11 in acute KD. Our aim was to determine the sLR11 dynamics in acute KD and to assess its usefulness as a biomarker.Methods and Results: 106 acute KD patients and 18 age-matched afebrile controls were enrolled. KD patients were classified into the following subgroups: intravenous immunoglobulin (IVIG) responders (n=85) and non-responders (n=21). Serum sLR11 levels before IVIG therapy were higher in non-responders (median, 19.6 ng/mL; interquartile range [IQR], 13.0-24.9 ng/mL) than in controls (11.9 ng/mL, 10.4-14.9 ng/mL, P<0.01) or responders (14.3 ng/mL, 11.7-16.5 ng/mL, P<0.01). Using a cutoff of >17.5 ng/mL, non-responders to initial IVIG therapy were identified with 66.7% sensitivity and 78.8% specificity. CONCLUSIONS: sLR11 can reflect the state of acute KD and might be a biomarker for patient response to IVIG therapy.

Genetic assessment using whole-exome sequencing for a young hypertriglyceridemic patient with repeated acute pancreatitis.

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.

Esterification of 4ß-hydroxycholesterol and other oxysterols in human plasma occurs independently of LCAT.

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4ß-hydroxycholesterol (4ßHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6ß-epoxycholesterol (5,6ßEC), 0.51; cholesterol, 0.70; cholestane-3ß,5α,6ß-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6ßEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4ßHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4ßHC. Substantial FA esterification of 4ßHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT.

Impact of LR11 as Residual Risk on Long-Term Clinical Outcomes in Patients with Coronary Artery Disease Treated with Statins after First Percutaneous Coronary Intervention.

Cardiovascular events still occur despite statin-based lipid-lowering therapy in patients with coronary artery disease (CAD). LR11, a member of the low-density lipoprotein receptor family, is a novel marker for the proliferation of intimal smooth muscle cells, which are critical to atherosclerotic plaque formation. We evaluated the impact of LR11 on long-term clinical outcomes in CAD patients treated with statins after percutaneous coronary intervention (PCI).This study included 223 consecutive CAD patients (age, 64.5 ± 9.6 years; male, 81.2%) treated with statin after first PCI between March 2003 and December 2004 at our institution. Patients were stratified to two groups according to LR11 levels (median). Composite cardiovascular disease (CVD) endpoints that included cardiovascular death, non-fatal acute coronary syndrome and non-fatal stroke were compared between groups.The rate of CVD endpoints was significantly higher in the high LR11 group (log-rank, P = 0.0029) during the median follow-up period of 2844 days. Multivariate Cox regression analysis showed that a higher LR11 level was significantly associated with adverse clinical outcomes (adjusted hazard ratio for composite CVD endpoints, 2.47; 95% confidence interval, 1.29-4.92; P = 0.006).Elevated levels of LR11 were significantly associated with long-term clinical outcomes among CAD patients treated with statins after first PCI.

Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with poor prognosis, because of no effective targeted therapy. In the present study, we demonstrated the crucial role of the aryl hydrocarbon receptor (AhR) in mediating the effects of the chemotherapeutic agent doxorubicin (DOX) in the chemotherapeutic sensitivity of TNBC. Firstly, we established AhR knockout (KO) MDA-MB 231 TNBC cells. The cytotoxic effects of DOX were more pronounced in AhR KO cells than in parental cells. In addition, our results indicated that AhR KO cells showed downregulated expression of DOX-metabolism enzyme, aldo-keto reductase (AKR) 1C3, relative to those of parental cells. Furthermore, AhR was found to enhance AKR1C3 promoter reporter activity, suggesting that AKR1C3 mRNA transcription is activated by AhR. Additionally, our findings confirmed that the downregulation of AKR1C3 expression enhanced DOX sensitivity in MDA-MB 231 cells. Finally, AhR and AKR1C3 expression were positively correlated in human breast cancer. Taken together, our results suggested that AhR is involved in DOX sensitivity by regulating AKR1C3 expression in TNBC cells.

Heregulin-induced cell migration is promoted by aryl hydrocarbon receptor in HER2-overexpressing breast cancer cells.

HER2 overexpression accounts for approximately 15-20% of all breast cancers. We have shown that HER2 overexpression leads to elevated expression of the aryl hydrocarbon receptor (AhR) in breast cancer cells. In this study, firstly, we showed that AhR expression was up-regulated by treatment with the HER3 ligand heregulin (HRG) in HER2-overexpressing breast cancer cell lines. Induction of AhR was mediated by transcriptional activation of the region of AhR promoter corresponding to - 190 to - 100 bp. In addition, HRG treatment elicited nuclear translocation of AhR. To investigate the role of AhR in HRG-HER2/HER3 signaling in HER2-overexpressing cells, we established AhR knockout (KO) HER2-overexpressing cells to perform wound-healing assays. HRG-induced cell migration was markedly attenuated by AhR KO. HRG-induced cell migration was associated with increased expression of the inflammatory cytokines interleukin (IL)-6 and IL-8 in wild type cells, but not in AhR KO cells. These results elucidate that AhR is an important factor for the malignancy in HER2 overexpressing breast cancers.

Regulation of secretion and enzymatic activity of lipoprotein lipase by C-mannosylation.

Lipoprotein lipase (LPL) is a crucial enzyme in lipid metabolism and transport, and its enzymatic deficiency causes metabolic disorders, such as hypertriglyceridemia. LPL has one predicted C-mannosylation site at Trp417. In this study, we demonstrated that LPL is C-mannosylated at Trp417 by mass spectrometry. Furthermore, by using wild-type and a C-mannosylation-defective mutant of LPL-overexpressing cell lines, we revealed that both secretion efficiency and enzymatic activity of C-mannosylation-defective mutant LPL were lower than those of wild-type. These data suggest the importance of C-mannosylation for LPL functions.

Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice.

OBJECTIVE: We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. APPROACH AND RESULTS: The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. CONCLUSIONS: LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension.

Soluble form of LR11 is highly increased in the vitreous fluids of patients with idiopathic epiretinal membrane.

PURPOSE: LR11 (also called SorLA or SORL1) is a migration regulator of adherent cells with the immature proliferative phenotype. The present study investigated the clinical and pathological involvement of the soluble form of LR11 (sLR11) in the idiopathic epiretinal membrane (iERM). METHODS: The subjects were 51 patients with iERM (24 cellophane macular reflex (CMR) and 27 preretinal macular fibrosis (PMF)) and 45 patients with macular holes as age and sex-matched controls. Vitreous sLR11 and transforming growth factor (TGF)ß2 levels were measured by ELISA. RESULTS: The sLR11 levels in the vitreous fluids of patients with iERM (20.2 ± 8.1 ng/mL) were significantly higher than those in controls (11.4 ± 4.7 ng/mL). Among the patients with iERM, the vitreous sLR11 levels were significantly higher in PMF (23.6 ± 8.2 ng/mL), than those in CMR (16.5 ± 5.9 ng/mL). Multivariate regression analysis of the studied factors showed that sLR11 was a unique factor independently contributing to the discrimination of the iERM patients against the control subjects (odds ratio [OR] 1.35 per 1-ng/mL increase, 95% CI 1.09-1.67; P = 0.004). ROC analysis showed that the sensitivity and the specificity of sLR11, but not of other studied factors, categorized into the rank of moderate accuracy. Finally, there was a positive correlation (R = 0.588; P = 0.003) between the vitreous levels of sLR11 and TGFß2 using the available samples. CONCLUSIONS: sLR11 levels in vitreous fluids were specifically increased in patients with iERM, suggesting the involvement in the pathology of proliferative and migrating cells for the development of iERM.

Human adipocytes from the subcutaneous superficial layer have greater adipogenic potential and lower PPAR-γ DNA methylation levels than deep layer adipocytes.

Human subcutaneous fat tissue consists of two layers, superficial adipose tissue (SAT) and deep adipose tissue (DAT). Some recent reports suggest that a disproportionate accumulation of DAT is related to obesity-associated metabolic complications. However, the differences in adipocyte function between SAT and DAT are unclear. To clarify the differences in human adipocyte characteristics between SAT and DAT, human ceiling culture-derived proliferative adipocytes (ccdPAs) were primary cultured from SAT and DAT of three lean female patients. Differences in adipogenic differentiation potential and sensitivity to exogenous adipogenic factors were examined. Epigenetic modification of the CpG island DNA methylation levels of genes related to adipogenesis was measured. In histological analyses, the mean adipocyte size in SAT was significantly larger than that in DAT (8,741 ± 416 vs. 7,732 ± 213 µm(2), P < 0.05). Primary cultured adipocytes from SAT showed significantly greater adipogenesis than did those of DAT. Sensitivity to partial adipogenic stimulation was significantly different between ccdPAs of SAT and DAT. Peroxisome proliferator-activated receptor-γ (PPAR-γ) protein expression and leptin protein secretion from ccdPAs were significantly higher in SAT than DAT. DNA methylation levels of PPAR-γ were significantly lower in ccdPAs of SAT than DAT. Adipocyte size was larger in SAT than DAT in vivo. This is consistent with the findings of an in vitro study that, compared with ccdPAs in DAT, ccdPAs in SAT have higher adipogenic potential and lower DNA methylation levels of PPAR-γ.

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Measuring local immunoglobulin E in the inferior turbinate nasal mucosa in patients with allergic rhinitis.

BACKGROUND: Studies show that immunoglobulin E (IgE) is produced in the local nasal mucosa in allergic rhinitis patients. However, no study involved the measurement of IgE levels in the local nasal mucosal tissue in allergic rhinitis patients. This study aimed to measure the local IgE levels in the nasal mucosal tissue and to compare the levels of total IgE and specific IgEs in the serum and the inferior turbinate nasal mucosa in allergic rhinitis patients using the AlaSTAT 3gAllergy assay (Siemens Healthcare Diagnostics AG, Erlangen, Germany). METHODS: Total IgE antibodies and allergen-specific IgE antibodies in each sample of nasal mucosal tissue from 11 allergic rhinitis patients were measured with the AlaSTAT 3gAllergy assay. We compared the levels of total IgE and IgEs specific for house dust (HD), mites, and cedar pollen in the serum and the inferior turbinate. RESULTS: The total IgE levels and the cedar pollen-specific IgE levels in the inferior turbinate mucosal tissue correlated significantly with their respective levels in serum. The HD- and mite-specific IgE levels in the inferior turbinate mucosal tissue did not correlate significantly with their respective levels in the serum. CONCLUSIONS: Our results evaluating the correlations between nasal mucosal and serum levels of antigen-specific IgE indicate that IgE produced in the nasal mucosa affects the IgE levels in the serum, especially the cedar pollen-specific IgE.

[Biomarkers for Atherosclerotic Diseases: Significance of Intimal Smooth Muscle Cell-Derived Circulating Marker].

Vascular cells with the active molecules they release are involved in the progression of atherosclerosis. These cell-related circulating markers are expected to reflect the pathological conditions of atherosclerotic lesions. In response to stimuli from other cells or active molecules, smooth muscle cells (SMCs) in the medial layer change their phenotype from contractile to synthetic, migrate from the media into the intima, and there they proliferate and release various kinds of cytokines, proteinases, and extra-cellular matrices. Thus, the functions of intimal SMCs are believed to play key roles in plaque formation. The incomplete or sustained activation of intimal SMCs may cause the fragility of plaques under pathological conditions, i.e., diabetes and dyslipidemia. LR11 is one of the genes specifically expressed in intimal SMCs, but not in me- dial SMCs, and it increases the sensitivity of intimal SMCs to migration in response to cytokines including angiotensin II. The soluble form of LR11 is in circulation, and the levels increase transiently after coronary intervention in the period corresponding to the migration of SMCs. The increase in initial sLR11 levels is negatively correlated with event-free survival for CVD endpoints. These results suggest that biomarkers reflecting the pathological conditions of intimal SMCs may be useful as surrogate and/or companion markers for the treatment of atherosclerotic diseases. [Review].

Low-dose radiation pretreatment improves survival of human ceiling culture-derived proliferative adipocytes (ccdPAs) under hypoxia via HIF-1 alpha and MMP-2 induction.

Poor survival is a major problem of adipocyte transplantation. We previously reported that VEGF and MMPs secreted from transplanted adipocytes are essential for angiogenesis and adipogenesis. Pretreatment with low-dose (5 Gy) radiation (LDR) increased VEGF, MMP-2, and HIF-1 alpha mRNA expression in human ceiling culture-derived proliferative adipocytes (hccdPAs). Gene expression after LDR differed between adipose-derived stem cells (hASCs) and hccdPAs. Pretreatment with LDR improved the survival of hccdPAs under hypoxia, which is inevitable in the early stages after transplantation. Upregulation of VEGF and MMP-2 after LDR in hccdPAs is mediated by HIF-1 alpha expression. Our results suggest that pretreatment with LDR may improve adipocyte graft survival in a clinical setting through upregulation of VEGF and MMP-2 via HIF-1 alpha.

Lipoprotein subfractions highly associated with renal damage in familial lecithin:cholesterol acyltransferase deficiency.

OBJECTIVE: In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. APPROACH AND RESULTS: Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large low-density lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. CONCLUSIONS: Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED. The abnormal lipoproteins were sensitive to treatment with recombinant LCAT and thus may play a causal role in the renal pathology of FLD.

The soluble form of LR11 protein is a regulator of hypoxia-induced, urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of immature hematological cells.

A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from the self-renewing quiescent to the proliferating stage is their adhesion to the bone marrow (BM) niche. An important molecule involved in proliferation and pool size of HSPCs in the BM is the hypoxia-induced urokinase-type plasminogen activator receptor (uPAR). Here, we show that the soluble form (sLR11) of LR11 (also called SorLA or SORL1) modulates the uPAR-mediated attachment of HSPCs under hypoxic conditions. Immunohistochemical and mRNA expression analyses revealed that hypoxia increased LR11 expression in hematological c-Kit(+) Lin(-) cells. In U937 cells, hypoxia induced a transient rise in LR11 transcription, production of cellular protein, and release of sLR11. Attachment to stromal cells of c-Kit(+) Lin(-) cells of lr11(-/-) mice was reduced by hypoxia much more than of lr11(+/+) animals. sLR11 induced the adhesion of U937 and c-Kit(+) Lin(-) cells to stromal cells. Cell attachment was increased by sLR11 and reduced in the presence of anti-uPAR antibodies. Furthermore, the fraction of uPAR co-immunoprecipitated with LR11 in membrane extracts of U937 cells was increased by hypoxia. CoCl2, a chemical inducer of HIF-1α, enhanced the levels of LR11 and sLR11 in U937 cells. The decrease in hypoxia-induced attachment of HIF-1α-knockdown cells was largely prevented by exogenously added sLR11. Finally, hypoxia induced HIF-1α binding to a consensus binding site in the LR11 promoter. Thus, we conclude that sLR11 regulates the hypoxia-enhanced adhesion of HSPCs via an uPAR-mediated pathway that stabilizes the hematological pool size by controlling cell attachment to the BM niche.

Effects of serotonin on expression of the LDL receptor family member LR11 and 7-ketocholesterol-induced apoptosis in human vascular smooth muscle cells.

Serotonin (5-HT) is a known mitogen for vascular smooth muscle cells (VSMCs). The dedifferentiation and proliferation/apoptosis of VSMCs in the arterial intima represent one of the atherosclerotic changes. LR11, a member of low-density lipoprotein receptor family, may contribute to the proliferation of VSMCs in neointimal hyperplasia. We conducted an in vitro study to investigate whether 5-HT is involved in LR11 expression in human VSMCs and apoptosis of VSMCs induced by 7-ketocholesterol (7KCHO), an oxysterol that destabilizes plaque. 5-HT enhanced the proliferation of VSMCs, and this effect was abolished by sarpogrelate, a selective 5-HT2A receptor antagonist. Sarpogrelate also inhibited the 5-HT-enhanced LR11 mRNA expression in VSMCs. Furthermore, 5-HT suppressed the 7KCHO-induced apoptosis of VSMCs via caspase-3/7-dependent pathway. These findings provide new insights on the changes in the differentiation stage of VSMCs mediated by 5-HT.

G-CSF induces the release of the soluble form of LR11, a regulator of myeloid cell mobilization in bone marrow.

Granulocyte colony-stimulating factor (G-CSF) induces the mobilization of leukocytes from the bone marrow (BM) to the circulation by a yet incompletely understood mechanism. Here, we describe that the membrane-bound receptor LR11 is highly expressed in human myeloid cells and that the shed soluble form of LR11 (sLR11) is a modifier of myeloid cell migration. In the process of leukocyte mobilization by G-CSF treatment, circulating sLR11 levels are transiently elevated in humans and mice. Moreover, following G-CSF treatment, the sLR11 levels in patients show significant positive correlation with the numbers of mobilized leukocytes. The changes of LR11 levels in BM cells and of sLR11 released into the BM fluid of mice correlate tightly with the changes in circulating sLR11 levels. G-CSF dose-dependently enhanced sLR11 release from HL-60 cells, which in turn accelerated cell migration. Finally, cooperatively with tumor necrosis factor-α (TNF-α) and G-CSF, sLR11 increased the attachment of floating cells (HL-60 and U937) to endothelial cells. We propose that sLR11 is a novel candidate modifier of G-CSF-mediated mobilization of hematologic cells. Identification of sLR11 as a regulatory component of G-CSF-mediated hematologic cell mobilization may facilitate further improvement of hematologic stem cell collection for clinical applications.

[Comparison of antioxidant capacities in serum and vitreous fluids of vitreoretinal diseases].

PURPOSE: To investigate serum antioxidant potential of patients with vitreoretinal diseases that require vitreous surgery and the antioxidant potential in vitreous fluids obtained intraoperatively. SUBJECTS AND METHODS: Twenty seven eyes of 27 patients who had undergone vitrectomy for macular edema associated with branch retinal vein occlusion (BRVO), proliferative diabetic retinopathy (PDR), macular hole (MH)/epiretinal membrane (ERM) at Toho University Sakura Medical Center were studied. The biological anti-oxidant potential (BAP), as an index of anti-oxidant potential of serum and vitreous fluid was measured using a free radical elective evaluator (FREE). RESULTS: The vitreous BAP levels (microEq/l) in the PDR group was 1843 +/- 402 and in the BRVO group, 2120 +/- 413. The BAP levels in the vitreous fluid of the PDR and BRVO were significantly lower than those of control subjects. The serum BAP levels (microEq/l) in the PDR group was 2307 +/- 51.9 and in the BRVO group, 2390 +/- 149. The serum BAP levels in the PDR group were significantly lower than those in the control group. Only in the PDR group, the serum BAP was significantly lower than the vitreous BAP. The vitreous BAP levels were significantly positively correlated with those of the serum. CONCLUSIONS: A difference was shown between the antioxidant potentials of the vitreous fluid and serum in the patients with PDR. Antioxidant potential in the eye had possibly declined in patients with ischemic vitreoretinal disease compared with other vitreoretinal diseases.

Diagnostic Value of sLR11 and sIL-2R in the Cerebrospinal Fluid for Malignant Central Nervous System Lymphoma.

Objective We previously reported that patients with acute leukemia and malignant lymphoma (ML) demonstrated significantly increased serum soluble LR11 (sLR11) levels compared to normal controls. Accurately diagnosing ML of the central nervous system (CNS ML) using cytology is frequently difficult. Therefore, we evaluated the use of cerebrospinal fluid (CSF) sLR11 and soluble interleukin-2 receptor (sIL-2R) as diagnostic and treatment response markers for CNS ML. Methods We retrospectively evaluated the CSF results for CNS ML using clinical data at our institution, and then analyzed the usefulness of sLR11 and sIL-2R in CSF for both the diagnosis and as surrogate markers that reflect the therapeutic effect. Patients We enrolled patients with CNS ML who received intrathecal anticancer drugs between 2017 and 2023. We analyzed the sLR11 and sIL-2R levels in CSF and cytological malignant grades. We studied 22 patients, including 17 with central nervous system (CNS) clinical conditions and five who received prevention treatment. Results The CSF sLR11 levels were significantly and positively correlated with CSF sIL-2R levels. The CSF sLR11 and sIL-2R levels in patients with CNS ML were significantly higher than those in the prevention group. A receiver operating characteristic (ROC) curve analysis showed the cut-off value of sLR11 for CNS invasion to be 21.7 ng/mL. Moreover, the chemotherapy-responder group demonstrated significantly decreased CSF sLR11 and sIL-2R levels after treatment. Conclusion CSF sLR11 and sIL-2R of CSF were found to be useful biomarkers for the diagnostic and treatment response evaluation in patients with CNS ML.