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Polymorphisms of endothelial nitric oxide synthases (eNOS) have been associated with cancer susceptibility. Also, metabolic syndrome is associated with cancer malignancy. However, the effect of eNOS polymorphisms and metabolic syndrome on colorectal cancer (CRC) prognosis remains unclear.To investigated whether three genetic polymorphisms (- 786 T C rs2070744, 4a4b rs869109213, and 894G T rs1799983) in the eNOS and metabolic syndrome (MetS) were associated with CRC patient survival.We genotyped three polymorphisms of eNOS (- 786 T C, 4a4b, and 894G T) in 312 CRC cases from the Korean population by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.Although the three eNOS polymorphisms were not causative of MetS, the TT genotype of the 894G T polymorphism was associated with a worse survival rate compared with the GG genotype in the CRC group with MetS than in the CRC group without MetS (5-years survival; adjusted HR = 54.777; 95% CI 5.073-591.487 and RFS; adjusted HR = 14.909; 95% CI 1.571-141.528).The eNOS polymorphisms were not associated with metabolic syndrome prevalence in CRC patients. However, our findings suggest that the eNOS 894G T polymorphism with MetS was associated with poor clinical outcomes.

To evaluate the safety and effectiveness of aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in Korean patients with metastatic colorectal cancer (mCRC) who progressed with oxaliplatin-containing regimen.This was a prospective observational study conducted at 22 sites across Korea between February 2018 and September 2019. Patients aged 19 years with a diagnosis of mCRC who were prescribed aflibercept plus FOLFIRI, after progression with an oxaliplatin-containing regimen were included. Disease assessment was performed every 6 weeks.A total of 185 patients were included (males, 58.9%; right-sided tumors, 23.8%; and ECOG performance factor ≥ 1, 68.6%). A total of 514 adverse events (AEs) occurred in 134 patients, of which 206 (49.2%; 95% CI 42.0%, 56.4%) events were considered as adverse drug reactions (ADRs), 172 unexpected AEs (49.7%; 95% CI 42.5%, 56.9%), and 53 serious AEs (22.2%; 95% CI16.2%, 28.2%). The most common serious ADR was pneumonia (n = 2, 1.6%). The most common all grade hematological AE and non-hematological AE were neutropenia (21.6%) and nausea (16.2%), respectively. Over a median follow-up of 5.6 months, a total of five grade 5 (1.0%) AEs were reported. Median OS was 9.4 months, and median progression-free survival (PFS) was 7.3 months. The overall response rate was 14.6%. Right-sided tumor location and prior bevacizumab treatment were independent factors of poor PFS in multivariate analysis.Aflibercept in combination with FOLFIRI was effective and showed an acceptable safety profile in Korean patients with mCRC in daily clinical practice.

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induces diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic subunit alpha and AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Background: Cardiovascular disease (CVD) is an inflammatory disorder enhanced by diabetes. The mechanisms by which recurrent acute hyperglycemia promotes inflammation and CVD are unclear. We showed that acute hyperglycemia mediates increased monocyte cholesterol uptake and cytokine release, but the underlying signaling pathways are unknown. We hypothesized that acute hyperglycemia-induced oxidative and ER stress in circulating monocytes increases cholesterol uptake and a pro-inflammatory phenotype. Methods: Circulating monocytes from 35 healthy subjects were isolated and exposed to euglycemic (5mM) or hyperglycemic (16.7 mM) conditions with or without inhibitors of ER stress (4 phenyl butyric acid) or oxidative stress (N-Acetyl cysteine) for 2 or 6 hrs to assess changes in LDL or oxLDL uptake and cytokine (TNF-α, IL1-β) release. Results: We found that acute hyperglycemia-induced ER and oxidative stress increased total and free cholesterol content via enhanced LDL (18% and 26%, p Conclusion: Recurrent acute hyperglycemia promotes inflammation by increasing monocyte ER and oxidative stress, which accelerates cholesterol uptake, cholesterol deposition, and cytokine secretion. Future studies are needed to test if acute hyperglycemia-induced monocyte cholesterol deposition is a mechanism to contribute to increased CVD in diabetes. Disclosure R.Zhang: Research Support; American Heart Association. J.Oh: None. G.A.Kutz: None. M.Bambouskova: None. A.S.Dusso: None. C.Bernal-mizrachi: None.

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, which results from uncontrolled complement activation. Delayed diagnosis and treatment of aHUS may result in end-stage renal disease (ESRD) and an associated dependence on dialysis. In extreme cases, it may cause death due to multi-organ failure. Eculizumab, a humanized monoclonal antibody against C5, inhibits the formation of the terminal membrane attack complex and is used to treat aHUS. Here, we report a 46-year-old male patient who suffered from aHUS relapse, despite prior treatment with repeated plasma exchange and hemodialysis. Eculizumab therapy improved his hematologic findings without use of hemodialysis. (Korean J Med 2020;95:124-128)

We examined the effects of empagliflozin, a selective inhibitor of Na+-glucose cotransporter 2, on mitochondrial quality control and autophagy in renal tubular cells in a diabetic environment in vivo and in vitro. Human renal proximal tubular cells (hRPTCs) were incubated under high-glucose conditions. Diabetes was induced with streptozotocin in male C57BL/6J mice. Improvements in mitochondrial biogenesis and balanced fusion-fission protein expression were noted in hRPTCs after treatment with empagliflozin in high-glucose media. Empagliflozin also increased autophagic activities in renal tubular cells in the high-glucose environment, which was accompanied with mammalian target of rapamycin inhibition. Moreover, reduced mitochondrial reactive oxygen species production and decreased apoptotic and fibrotic protein expression were observed in hRPTCs after treatment with empagliflozin, even in the hyperglycemic circumstance. Importantly, empagliflozin restored AMP-activated protein kinase-α phosphorylation and normalized levels of AMP-to-ATP ratios in hRPTCs subjected to a high-glucose environment, which suggests the way that empagliflozin is involved in mitochondrial quality control. Empagliflozin effectively suppressed Na+-glucose cotransporter 2 expression and ameliorated renal morphological changes in the kidneys of streptozotocin-induced diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased and 8-hydroxy-2′-deoxyguanosine content was low in renal tubular cells of empagliflozin treatment groups compared with those of the diabetic control group. We suggest one mechanism related to the renoprotective actions of empagliflozin, which reverse mitochondrial dynamics and autophagy.

Interpolation inequalities in Triebel-Lizorkin-Lorentz spaces and Besov-Lorentz spaces are studied for both inhomogeneous and homogeneous cases. First we establish interpolation inequalities under quite general assumptions on the parameters of the function spaces. Several results on necessary conditions are also provided. Next, utilizing the interpolation inequalities together with some embedding results, we prove Gagliardo-Nirenberg inequalities for fractional derivatives in Lorentz spaces, which do hold even for the limiting case when one of the parameters is equal to 1 or $\infty$., Comment: 47 pages

Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b−/− bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension., Myeloid cells are involved in hypertension, but their exact role in renin-induced hypertension remains unclear. Here the authors show that impaired vitamin D signaling in myeloid cells causes hypertension via macrophage-specific miR-106b-5p secretion, which activates renin production in the kidney.

Ethnopharmacological relevance Artemisia scoparia Waldst. & Kitam (A. scoparia) is a perennial herbal plant that is widely used as a folk remedy in Asian countries. Several studies have demonstrated that A. scoparia has various physiological effects, including anti-inflammation, anti-hypertension, anti-obesity, anti-hepatotoxicity, and anti-oxidant effects. Aim of the study: The objective of the present study was to examine the anti-inflammatory effects of water extract of A. scoparia (WAS). Materials and methods Murine bone marrow-derived macrophages (BMDMs), human monocyte THP-1 and murine fibroblast 3T3-L1 cells were used for the in vitro experiments. Cell viability and cytokine production were determined by the MTT assay and ELISA, respectively. RT-PCR was performed to determine iNOS gene expression and the Griess reaction was used to measure nitrite levels. iNOS protein expression, activation of NF-κB and MAPKs, and cleavage of caspase-1 and IL-1β were determined by Western blot analysis. A carrageenan-induced mouse model of acute inflammation was used in the in vivo experiments. Results Pretreatment with WAS concentration-dependently suppressed gene expression and IL-6, TNF-α, CXCL1 and iNOS protein levels in BMDMs stimulated with LPS. In addition, pretreatment with WAS inhibited LPS-induced production of IL-6 and TNF-α in THP-1 cells and CXCL1 in 3T3-L1. Furthermore, LPS induced phosphorylation of p65 in BMDMs, and this induction was dramatically suppressed by WAS pretreatment. We further investigated whether WAS regulates activation of the NLRP3 inflammasome, which is known to be essential for IL-1β processing. WAS inhibited the production of IL-1β, but not IL-6, in response to adenosine triphosphate (ATP) and monosodium uric acid (MSU) crystals in LPS-primed BMDMs. Cleavage of caspase-1 and IL-1β was also reduced by WAS. We finally evaluated the in vivo anti-inflammatory effects of WAS in a mouse model of carrageenan-induced acute inflammation. Subcutaneous administration of WAS reduced production of the inflammatory cytokines IL-6, TNF-α, CXCL1, and IL-1β. Recruitment of immune cells, mostly neutrophils, was also reduced by administration of WAS. Infiltration of inflammatory cells and edema in the submucosa of air pouch tissues were markedly improved in the WAS-treated groups. Conclusions Our results indicate that WAS possesses potent anti-inflammatory properties. These findings suggest that A. scoparia is a candidate functional food targeting several inflammatory diseases.

Background: Type 2 diabetes is linked to accelerated atherosclerosis, however the mechanisms behind this association are unclear. Inadequate glycemic control is an important contributor for cardiovascular disease (CVD). Episodic hyperglycemia as a surrogate for glycemic variability (GV) promotes monocyte adhesion and increases proinflammatory monocytes within plaques of patients with diabetes. Monocytes are precursors to macrophages which play a vital role in atherosclerosis and are capable of delivering cholesterol content to plaques. Therefore, elucidating the mechanism by which acute hyperglycemia promotes proatherogenic monocytes in diabetes can lead to novel therapies slowing atherosclerosis progression in these patients. Methods: To assess the effects of acute hyperglycemia on monocyte cholesterol metabolism, we isolated monocytes from 28 patients with Type 2 diabetes cultured for 2 and 6 hours in normoglycemic (90mg/dL) or hyperglycemic media (300mg/dL). Cholesterol content was measured by lipid extraction and fluorometric cholesterol oxidase assay. Cholesterol uptake was assessed by incubating monocytes with Dil-oxidized LDL (Dil-OxLDL). Cholesterol synthesis was performed by incubating monocytes with 2-14C-Acetate in both glycemic conditions for 6 hours followed by lipid saponification, and separated via TLC on silica gel plates. Cholesterol efflux was assessed by labeling cells with 3H-Cholesterol-OxLDL in both glycemic conditions for 6 hours followed by APO-A1 or HDL stimulation for 4 hours. Results: Acute hyperglycemia for 2 and 6 hours induced foamy monocytes with increased total cholesterol content (22 and 32%, respectively), cholesterol ester (40% and 43%, respectively), and free cholesterol content (14% and 25%, respectively) due to enhanced DiI-OxLDL uptake. There was no significant increase in monocyte cholesterol synthesis or cholesterol efflux after stimulation with HDL or APO A-1. Conclusions: Increased monocyte cholesterol content during acute hyperglycemia is a potential mechanism promoting atherosclerosis in patients with Type 2 diabetes.

Six new 8-C-p-hydroxybenzylflavonol glycosides were isolated from a hot water extract of pumpkin (Cucurbita moschata Duch.) tendril and elucidated as 8-C-p-hydroxybenzylquercetin 3-O-rutinoside, 8-C-p-hydroxybenzoylquercetin 3-O-&beta, D-glucopyranoside, 8-C-p-hydroxybenzylkaempferol 3-O-(&alpha, L-rhamnopyranosyl(1&rarr, 6)-&beta, D-galactopyranoside, 8-C-p-hydroxybenzoylkaempferol 3-O-rutinoside, 8-C-p-hydroxybenzylisorhamnetin 3-O-rutinoside, and 8-C-p-hydroxybenzylisorhamnetin 3-O-(&alpha, D-galactopyranoside. Their chemical structures were determined using nuclear magnetic resonance (NMR) and electrospray ionization-mass spectrometer (ESIMS) analyses. The 8-C-p-hydroxybenzylflavonol glycosides were found to inhibit the receptor activator of nuclear factor-&kappa, B (RANKL)-induced osteoclast differentiation of bone marrow derived macrophage (BMDM), an osteoclast progenitor. Additionally, 8-C-p-hydroxybenzylflavonol glycosides effectively reduced the expression of osteoclast-related genes, such as tartrate-resistant acid phosphatase, cathepsin K, nuclear factor activated T-cell cytoplasmic 1, and dendritic cell specific transmembrane protein in RANKL-treated BMDMs. These results indicate that the 8-C-p-hydroxybenzylflavonol glycosides may be the main components responsible for the osteoclast differentiation inhibitory effect of pumpkin tendril.

Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS. Materials and methods Sixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [CFH, CFB, CFI, CD46, C3, THBD, PLG, and DGKE] and seven candidate genes [CFP, C4BPA, and CHFR1-5]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions. Results Thirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/CFHR1 homozygous deletions. Conclusions The genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS.

Cross-sectional studies indicate consistent associations between low 25(OH)D concentration and increased risk of cardiovascular disease (CVD), but results of randomized control trials (RCTs) are mixed. However, the majority of the RCTs do not focus on type 2 diabetics, potentially obscuring the effects of vitamin D in this population. In vitro 1,25(OH)2D3 downregulates macrophage cholesterol deposition, but the in vivo effects are unknown. To explore potential mechanisms of the effects of vitamin D on CVD risk in patients with type 2 diabetes, we isolated monocytes in a subset of 26 patients from our RCT of diabetics with baseline serum 25(OH)D 50% reduction in the vitamin D group with no change in the placebo group. This was mediated through suppression of endoplasmic reticulum stress and scavenger receptor CD36 protein expression. The reduction in monocyte cholesterol uptake was reflected in a 19% decrease in total monocyte cholesterol content. Interestingly, cross-sectional analysis of circulating monocytes from vitamin D-deficient vs. sufficient diabetic patients revealed 8-fold higher cholesteryl ester content, confirming the capacity of these monocytes to uptake and carry cholesterol in the circulation. This study identifies a unique circulating cholesterol pool within monocytes that is modulated by vitamin D and has the potential to contribute to CVD in type 2 diabetes.

Chronic inflammation and local activation of the renin-angiotensin-aldosterone system (RAAS) play a pivotal role in the pathogenesis and progression of diabetic complications. In patients with type 2 diabetes (T2DM), the prevalence of vitamin D deficiency is almost twice that of non-diabetics, and vitamin d deficiency nearly doubles the risk of developing hypertension and cardiovascular complications compared to diabetics with normal vitamin D levels. Interestingly, mice lacking the vitamin D receptor (VDR) in macrophages (KODMAC) develop renin-dependent hypertension, insulin resistance, and inflammation via up-regulation of macrophage ER stress. Macrophages also express all major components of the RAAS system. However, little is known about the regulation of macrophage-generated renin and its role in modulating the sequelae of VDR signaling in macrophage function and cytokine production. This study found that KODMAC macrophages and vitamin D-deficient macrophages have increased expression and secretion of renin, angiotensin II, ACE, and AT1 receptor and that adhesion, migration, and cytokine release were also increased. Inhibition of ER stress in KODMAC macrophages and vitamin D-deficient macrophages with 4-Phenylbutyric acid (PBA) reduced RAS gene expression and macrophage pro-inflammatory phenotype. Renin 1c gene deletion decreased macrophage adhesion, migration, and cytokine release compared to macrophages with disrupted VDR signaling. Notably, disruption of VDR signaling induced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression in macrophages, and upregulation of renin expression in response to vitamin D deficiency was blunted in PCG1α-deficient macrophages. In conclusion, our findings delineate a mechanism by which impaired VDR signaling induces ER stress to drive PGC1α-dependent expression of renin and RAAS hyperactivation, thereby altering macrophage function and cytokine production. These data implicate RAAS as an essential mediator of VDR-mediated macrophage function and support ongoing investigations of VDR and RAAS modulation as therapeutic approaches in the management of T2DM and its complications.

Venous thromboembolism (VTE) involves the formation of a blood clot, typically in the deep veins of the leg or arm (deep vein thrombosis), which then travels via the circulatory system and ultimately lodges in the lungs, resulting in pulmonary embolism. A number of microRNAs (miRNAs) are well-known regulators of thrombosis and thrombolysis, and mutations in miRNA biogenesis genes, such as DICER1, DROSHA have been implicated in miRNA synthesis and function. We investigated the genetic association between polymorphisms in four miRNA biogenesis genes, DICER1 rs3742330A &gt, G, DROSHA rs10719T &gt, C, RAN rs14035C &gt, T and XPO5 rs11077A &gt, C, and VTE in 503 Koreans: 300 controls and 203 patients. Genotyping was assessed with polymerase chain reaction-restriction fragment length polymorphism assays. We detected associations between polymorphisms in RAN and XPO5 and VTE prevalence (RAN rs14035CC + CT versus TT: p = 0.018, XPO5 rs11077AA + AC versus CC: p &lt, 0.001). Analysis of allele combinations of all four polymorphisms (DICER1, DROSHA, RAN, XPO5) revealed that A-T-T-A was associated with decreased VTE prevalence (p = 0.0002), and A-T-C-C was associated with increased VTE prevalence (p = 0.027). Moreover, in subjects with provoked VTE, the DROSHA rs10719T &gt, C, polymorphism was associated with increased disease prevalence (TT versus TC + CC: p &lt, 0.039). Our study demonstrates that RAN and XPO5 polymorphisms are associated with risk for VTE in Korean subjects.

Background Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. Although these conditions are difficult to differentiate clinically, TTP can be distinguished by low (

Diabetes is a chronic inflammatory disease that accelerate cardiovascular disease (CVD). However, the contribution of hyperglycemia to inflammation and CVD risk is unclear. Animal studies have shown that monocytes carry cholesterol to the atherosclerotic plaque. Thus, it is key to determine if hyperglycemia can exert a pro-atherogenic effect in human monocytes in vivo. We performed octreotide euglycemic-hyperglycemic clamps in 21 healthy subjects, 20-45 yo. Monocytes isolated during euglycemia (90 mg/dl) and after 2h of hyperglycemia (300 mg/dl) were evaluated for cholesterol metabolism and monocyte function (adhesion to fibronectin, transwell migration assays). Also, we assessed the effects of hyperglycemia on monocyte cholesterol metabolism and function from 10 healthy controls cultured in euglycemia or high glucose media with or without 2-deoxyglucose (2DG) at 2 and 6 hours. Acute hyperglycemia in vivo increased 37% total monocyte cholesterol content (TC) (p Disclosure R.M. Zhang: None. J. Oh: None. X. Lin: None. P. Stone: None. K.J. Wharton: None. A. Arbelaez: None. C. Bernal-Mizrachi: None. Funding National Heart, Lung, and Blood Institute (R01HL094818-06); National Institute of Neurological Disorders and Stroke (P01NS080675)

Background Recent studies have extensively investigated the role of miRNAs in colorectal cancer (CRC), and several associations have been reported. In addition, single nucleotide polymorphisms (SNPs) in promoter regions of miRNAs have been shown to affect miRNA expression. Therefore, we aimed to analyze the effect of miRNA polymorphisms on CRC susceptibility. Methods We conducted association studies on the relationships between the miRNA polymorphisms miR-130bT > C rs373001, miR-200bT > C rs7549819, and miR-495A > C rs2281611 and CRC with 472 CRC patients and 399 control subjects in Korea. Results Multivariate logistic regressions of the CRC subgroups showed that the miR-495CC genotype associated with rectal cancer (AA+AC vs. CC; adjusted odds ratio (AOR) for CC, 1.592; 95% confidence interval (CI), 1.071–2.368; P = 0.022). The gene-environment combinatorial analysis showed that the combination of miR-495A > C and low plasma folate contributed to an increased risk of rectal cancer (AA+AC vs. CC; AOR for CC, 3.829; 95% CI, 1.577–9.300; P = 0.003). In the survival analysis, miR-200bT > C associated with CRC patient mortality (TT vs TC + CC; adjusted hazard ratio for TC + CC, 0.592; 95% CI, 0.373–0.940; P = 0.026). Conclusion In this study, we found that miR-200b and miR-495 polymorphisms are involved in CRC susceptibility and prognosis. Electronic supplementary material The online version of this article (10.1186/s12885-019-5641-1) contains supplementary material, which is available to authorized users.

Background: Vitamin D deficiency is prevalent in pregnant women and their offspring. Maternal vitamin D deficiency is associated with insulin resistance in children and can induce a proinflammatory macrophage phenotype [1, 2]. Purpose: We hypothesized that maternal vitamin D deficiency induces immune cell reprogramming that promotes adipose insulin resistance in the offspring and is detectable in the newborn period. Methods: We enrolled 32 normal pregnant women prior to delivery of AGA, term infants. Cord blood was obtained and used to determine vitamin D [25(OH)D] levels and qPCR of microRNA levels. Cord blood monocytes were co-cultured with 3T3L1 adipocytes for insulin-stimulated 2-deoxyglucose uptake studies, and the monocyte media and co-cultured adipocytes were analyzed for microRNA expression. 3T3L1 adipocytes were transfected with miR106b mimic and antagonist to confirm the effect of the 2-deoxyglucose results. Results: 83% of the newborn’s venous cord blood showed vitamin D deficiency with 25(OH)D

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

Table S1. Information of miR-200 and 495 polymorphisms for PCR-RFLP. Table S2. Comparison of genotype frequencies of microRNA polymorphisms between colorectal cancer subtype and control. Table S3. Stratified effects of miR-130bT > C, miR-200bT > C, and miR-495C > A polymorphisms on CRC susceptibility. Table S4. Combinatorial effects of miRNA polymorphisms and environmental factors on CRC risk. (DOCX 26 kb)

Introduction: Poor glycemic control is considered an important contributor to cardiovascular disease in patients with diabetes. Episodic hyperglycemia as a surrogate for glycemic variability promotes monocyte adhesion and increases the prevalence of proinflammatory monocytes within atherosclerotic plaques of patients with diabetes. We previously found that acute hyperglycemia-induced a pro-inflammatory phenotype and promoted the development of foamy monocytes by increasing total cholesterol deposition, cholesterol ester, and free cholesterol content by enhancing oxidized LDL uptake. However, the mechanism by which acute hyperglycemia induces monocyte cholesterol deposition and inflammation remains unknown. Methods: Monocytes isolated from healthy individuals (age range 20–40; n=5) were cultured in low (5mM) or high (16.7mM) glucose conditions with or without a glycolysis inhibitor (2-deoxyglucose, 2DG, 5 mM) or an endoplasmic reticulum stress inhibitor (4-phenylbutyric acid, PBA; 20mM) for 6 hrs. After treatment, cytokine release, oxidized LDL uptake, and metabolic assays using Seahorse Technology were performed. Results: Healthy human monocytes exposed under high glucose conditions showed a pro-atherosclerotic phenotype with higher levels of the pro-inflammatory cytokines, TNFα(median of differences 6.34 pg/ml, p=0.002) and IL1β(12.04 pg/ml, p=0.003), and increased oxidized LDL uptake (5062ug Dil-Ox LDL/mg, p=0.001). Furthermore, hyperglycemia resulted in higher levels of glycolysis (basal glycolysis 12.94 pmol/min, p=0.01; basal proton efflux rate 15.5 pmol/min, p=0.03) and mitochondrial respiration (percentage of respiratory capacity 16pmol/min p=0.04), suggesting a significant alteration in the metabolic programming of these monocytes. Treatment with 2-DG or PBA attenuated the pro-atherosclerotic phenotype induced by hyperglycemia, promoting a reduction of cytokine release, a reduction of oxidized LDL uptake, and near normalization of the glycolic rate and mitochondrial respiration, stabilizing cellular bioenergetics. Conclusions: Altogether, our results suggest that monocyte ER stress in response to acute hyperglycemia promotes a hypermetabolic state characterized by a proinflammatory and proatherogenic monocyte phenotype. Therefore, acute hyperglycemia is a potential mechanism promoting atherosclerosis in patients with type 2 diabetes.

Hyun Chang,1,2,* Jisu Oh,1,3,* Xianglan Zhang,4 Yu Jung Kim,1 Jae Ho Lee,1 Choon-Taek Lee,1 Jin-haeng Chung,5 Jong-Seok Lee1 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, 2Division of Medical Oncology, Department of Internal Medicine, International St Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon, 3Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 4Department of Pathology, Yanbian University Hospital, Yanji, People’s Republic of China; 5Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea *These authors contributed equally to this work Purpose: The aim of this research was to examine the molecular and clinical features that are related with EGFR-tyrosine kinase inhibitor (EGFR-TKI) efficacy in previously treated patients with squamous cell carcinoma of the lung (SCCL). Materials and methods: This retrospective study included 67 SCCL patients with obtainable lung cancer tissue and records on EGFR-TKI treatment response and survival. EGFR protein expression in lung cancer tissue was measured by immunohistochemistry with a specific antibody that recognizes the intracellular domain (ID) of EGFR. PTEN expression in lung cancer tissue was also evaluated with immunohistochemistry. PI3KCA gene amplification was detected by quantitative real-time polymerase chain reaction, and FGFR1 amplification was assessed by fluorescent in situ hybridization. Results: EGFR ID expression (hazard ratio [HR] 0.53, P=0.022) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (HR 0.43, P=0.022) were significantly related with progression-free survival following EGFR-TKIs treatment. PTEN expression (HR 0.52, P=0.025) was significantly related to overall survival. The group of EGFR-positive or PTEN-positive patients with ECOG PS of 0 or 1 had better clinical outcomes than patients who were EGFR-negative and PTEN-negative or who had poor ECOG PS with longer median progression-free survival (2.1 vs 1.0months, P=0.05) and overall survival (6.2 vs 2.1months, P=0.05). Conclusion: EGFR expression using an ID-specific antibody and PTEN protein expression may be used to identify SCCL patients who might benefit from EGFR-TKI treatment. Keywords: EGFR, tyrosine kinase inhibitor, squamous cell carcinoma, lung, intracellular domain, PTEN

비록 자궁경부암이 갑상선으로의 전이는 매우 드물지만, 자궁경부암의 과거력이 있는 경우, 갑상선부위의 부종이나 촉지되는 결절이 발생하면 반드시 전이성 병변을 의심해봐야 한다. 비록 갑상선으로의 전이는 매우 나쁜 예후를 의미 하지만 고식적 치료로 전신항암요법 및 방사선요법이 환자의 삶의 질 개선에 도움을 줄 수 있다. 드물기는 하지만 갑상선으로의 악성전이 보고가 증가하는 추세로, 이에 대해 어떠한 치료가 가장 효과적일지에 대한 연구가 필요하겠다.

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (&minus, 844G&gt, A [rs2227631], &minus, 675 4G&gt, 5G [rs1799889], +43G&gt, A [rs6092], +9785G&gt, A [rs2227694], and +11053T&gt, G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 &minus, 675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556, 95% confidence interval (CI): 1.012&ndash, 2.391, p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620, 95% CI: 0.413&ndash, 0.932, p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662, 95% CI: 0.469&ndash, 0.933, p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism-related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS (1494del6 and the TS enhancer region (TSER)) and RFC1 (-43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction-restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism-related polymorphisms and CRC risk were identi- fied in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ≤4.12 ng/ml were associated with signif- icantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism-related genes combined with metabolic syndrome risk factors (hyper- tension and DM) increase the odds of developing CRC.

The c-Jun N-terminal kinase 2 (JNK2) signaling pathway contributes to inflammation and plays a key role in the development of obesity-induced insulin resistance and cardiovascular disease. Macrophages are key cells implicated in these metabolic abnormalities. Active vitamin D downregulates macrophage JNK activation, suppressing oxidized LDL cholesterol uptake and foam cell formation and promoting an anti-inflammatory phenotype. To determine whether deletion of JNK2 prevents high blood pressure and atherosclerosis known to be induced by vitamin D deficiency in mice, we generated mice with knockout of JNK2 in a background susceptible to diet-induced atherosclerosis (LDLR(−/−)). JNK2(−/−) LDLR(−/−) and LDLR(−/−) control mice were fed vitamin D-deficient chow for 8 weeks followed by vitamin D-deficient high fat diet (HFD) for 10 weeks and assessed before and after HFD. There was no difference in fasting glucose, cholesterol, triglycerides, or free fatty acid levels. However, JNK2(−/−) mice, despite vitamin D-deficient diet, had 20–30 mmHg lower systolic (SBP) and diastolic (DBP) blood pressure before HFD compared to control mice fed vitamin D-deficient diets, with persistent SBP differences after HFD. Moreover, deletion of JNK2 reduced HFD-induced atherosclerosis by 30% in the proximal aorta when compared to control mice fed vitamin D-deficient diets. We have previously shown that peritoneal macrophages obtained from LDLR(−/−) mice fed vitamin D-deficient HFD diets have higher foam cell formation compared to those from mice on vitamin D-sufficient HFD. The increased total cellular cholesterol and modified cholesterol uptake in macrophages from mice on vitamin D-deficient HFD were blunted by deletion of JNK2. These data suggest that JNK2 signaling activation is necessary for the atherosclerosis and hypertension induced by vitamin D deficiency.

Cross-sectional studies indicate consistent associations between low 25(OH)D concentration and increased risk of cardiovascular disease (CVD), but results of randomized control trials (RCTs) are mixed. However, the majority of the RCTs do not focus on type 2 diabetics, potentially obscuring the effects of vitamin D in this population. In vitro 1,25(OH)(2)D(3) downregulates macrophage cholesterol deposition, but the in vivo effects are unknown. To explore potential mechanisms of the effects of vitamin D on CVD risk in patients with type 2 diabetes, we isolated monocytes in a subset of 26 patients from our RCT of diabetics with baseline serum 25(OH)D 50% reduction in the vitamin D group with no change in the placebo group. This was mediated through suppression of endoplasmic reticulum stress and scavenger receptor CD36 protein expression. The reduction in monocyte cholesterol uptake was reflected in a 19% decrease in total monocyte cholesterol content. Interestingly, cross-sectional analysis of circulating monocytes from vitamin D-deficient vs. sufficient diabetic patients revealed 8-fold higher cholesteryl ester content, confirming the capacity of these monocytes to uptake and carry cholesterol in the circulation. This study identifies a unique circulating cholesterol pool within monocytes that is modulated by vitamin D and has the potential to contribute to CVD in type 2 diabetes.

Supporting timely data services using fresh data in data-intensive real-time applications, such as e-commerce and transportation management is desirable but challenging, since the workload may vary dynamically. To control the data service delay to be below the specified threshold, we develop a predictive as well as reactive method for database admission control. The predictive method derives the workload bound for admission control in a predictive manner, making no statistical or queuing-theoretic assumptions about workloads. Also, our reactive scheme based on formal feedback control theory continuously adjusts the database load bound to support the delay threshold. By adapting the load bound in a proactive fashion, we attempt to avoid severe overload conditions and excessive delays before they occur. Also, the feedback control scheme enhances the timeliness by compensating for potential prediction errors due to dynamic workloads. Hence, the predictive and reactive methods complement each other, enhancing the robustness of real-time data services as a whole. We implement the integrated approach and several baselines in an open-source database. Compared to the tested open-loop, feedback-only, and statistical prediction + feedback baselines representing the state of the art, our integrated method significantly improves the average/transient delay and real-time data service throughput.

Macrophages are essential in atherosclerosis progression, but regulation of the M1 versus M2 phenotype and their role in cholesterol deposition are unclear. We demonstrate that endoplasmic reticulum (ER) stress is a key regulator of macrophage differentiation and cholesterol deposition. Macrophages from diabetic patients were classically or alternatively stimulated and then exposed to oxidized LDL. Alternative stimulation into M2 macrophages lead to increased foam cell formation by inducing scavenger receptor CD36 and SR-A1 expression. ER stress induced by alternative stimulation was necessary to generate the M2 phenotype through JNK activation and increased PPARγ expression. The absence of CD36 or SR-A1 signaling independently of modified cholesterol uptake decreased ER stress and prevented the M2 differentiation typically induced by alternative stimulation. Moreover, suppression of ER stress shifted differentiated M2 macrophages toward an M1 phenotype and subsequently suppressed foam cell formation by increasing HDL- and apoA-1-induced cholesterol efflux indicating suppression of macrophage ER stress as a potential therapy for atherosclerosis.

It is essential to process real-time data service requests such as stock quotes and trade transactions in a timely manner using fresh data, which represent the current real-world phenomena such as the stock market status. Users may simply leave when the database service delay is excessive. Also, temporally inconsistent data may give an outdated view of the real-world status. However, supporting the desired timeliness and freshness is challenging due to dynamic workloads. To address the problem, we present new approaches for 1) database backlog estimation, 2) fine-grained closed-loop admission control based on the backlog model, and 3) incoming load smoothing. Our backlog estimation and control-theoretic approaches aim to support the desired service delay bound without degrading the data freshness, critical for real-time data services. Specifically, we design, implement, and evaluate two feedback controllers based on linear control theory and fuzzy logic control theory, to meet the desired service delay. Workload smoothing, under overload, helps the database admit and process more transactions in a timely fashion by probabilistically reducing the burstiness of incoming data service requests. In terms of the data service delay and throughput, our closed-loop admission control and probabilistic load smoothing schemes considerably outperform several baselines in the experiments undertaken in a stock trading database testbed.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). In type 2 diabetics, the prevalence of vitamin D deficiency is 20% higher than in non-diabetics, and low vitamin D levels nearly double the relative risk of developing CVD compared to diabetic patients with normal vitamin D levels. However, the mechanism(s) by which vitamin D deficiency leads to an increased susceptibility to atherosclerosis in these patients is unknown. We studied the effects of vitamin D replacement on macrophage cholesterol metabolism and foam cell formation in obese, hypertensive diabetics and non-diabetic controls. We found that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] suppressed foam cell formation by reducing acetylated low density lipoprotein (AcLDL) and oxidized low density lipoprotein (oxLDL) cholesterol uptake in diabetics only. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARgamma and CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxLDL- and AcLDL-derived cholesterol uptake. The results of this research reveal novel insights into the mechanisms linking vitamin D signaling to foam cell formation in diabetics and suggest a potential new therapeutic target to reduce cardiovascular risk in this population.