Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis.

BACKGROUND: The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor ß-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. METHODS: Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. RESULTS: KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. CONCLUSION: KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.

Iodine status and its association with prevalence of thyroid diseases in adults from Jiangxi Province, China.

BACKGROUND: Iodine is an essential element for the biosynthesis of thyroid-stimulating hormone (TSH). Both excessive and deficient iodine are major risk factors for thyroid diseases, including thyroid dysfunction, thyroid nodules, and thyroid autoimmunity (TAI). This study aimed to elucidate the relationship between iodine status and the prevalence of thyroid diseases through a national cross-sectional epidemiological survey in Jiangxi province (China). METHODS: This population-based, cross-sectional study enrolled 2636 Chinese local inhabitants who aged over 18 years old from April to August in 2015. Physical examination was performed and biochemical indices, urinary iodine concentration (UIC), and TSH level were measured. The Chi-square test, nonparametric test, and 4 multivariate logistic regression models adjusted for risk factors were applied to analysis. Spearman correlation coefficients were calculated to investigate the relationship between iodine intake level and the prevalence of thyroid diseases. RESULTS: The median UIC was 176.4 µg/L, and a significant difference was found in median UIC between men (182.45 µg/L) and women (169.25 µg/L) (P = 0.03). Among these study subjects, 14.4%, 44.5%, 26.1%, and 15.0% had deficient, adequate, more than adequate, and excessive iodine concentrations, respectively. The prevalence rates of hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, subclinical hypothyroidism, thyroid nodules, and TAI were 0.91%, 0.57%, 0.34% and 7.89%, 9.45%, and 12.7%, respectively. Significant differences were found in iodine status, waist circumstance, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), TSH, thyroid nodules, and TAI between men and women (P < 0.05). Compared with those with adequate UIC, subjects with excessive UIC had higher prevalence rates of thyroid dysfunction (odds ratio (OR) = 1.74, 95% confidence interval (CI): 1.40-2.54) and thyroid nodules (OR = 3.33, 95%CI 1.32-8.42). In addition, subjects with deficient and excessive UIC were at the higher risk of TAI compared with those with adequate UIC (OR = 1.68, 95%CI: 1.19-2.60; OR = 1.52, 95%CI: 1.04-2.96, respectively). UIC was positively correlated with the prevalence rates of thyroid nodules (r = -0.44, P < 0.01) and TAI (r = -0.055, P < 0.01). On the contrary, UIC was negatively correlated with the risk of thyroid dysfunction (r = -0.24, P > 0.05). CONCLUSION: Adult inhabitants from Jiangxi province in the TIDE study were in the adequate iodine status. Excessive iodine status was noted as a risk factor for thyroid dysfunction and thyroid nodules. In addition, both iodine deficiency and excessive iodine were risk factors for TAI.

Renal venous sampling assisted the diagnosis of juxtaglomerular cell tumor: a case report and literature review.

Juxtaglomerular cell tumor (JCT) is an endocrine tumor marked by elevated renin levels and high blood pressure. This case report presents the clinical findings of a 47-year-old woman with a history of recurrent hypokalemia, headaches, hypertension, and increased plasma renin activity (PRA). Dynamic enhanced magnetic resonance imaging (MRI) revealed a small nodule on the upper part of the right kidney. Selective renal venous sampling indicated a higher PRA only in the right upper pole renal vein. The patient underwent surgical removal of the right kidney mass, and the pathology results confirmed the diagnosis of JCT. This case underscores the importance of conducting selective renal venous sampling for accurate JCT diagnosis.

O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.

Differential Subsampling with Cartesian Ordering Contrast-Enhanced Magnetic Resonance Angiography for the Preoperative Assessment of Anterolateral Thigh Flap.

OBJECTIVE: To investigate the clinical application of differential subsampling with Cartesian ordering (DISCO) contrast-enhanced (CE) magnetic resonance angiography for anterolateral thigh (ALT) flap transplantation, using operative findings as a reference. MATERIALS AND METHODS: Thirty patients (21 males and nine females; mean age ± standard deviation, 45.5 ± 15.6 years) who were scheduled to undergo reconstruction with ALT flaps between June 2020 and June 2021 were included in the prospective study. Before ALT flap transplantation, patients were scanned using CE-DISCO imaging. All acquired DISCO images of the 60 lower limbs (both sides from each patient) were analyzed using maximum intensity projection and volume rendering methods. Two experienced radiologists were employed to examine the patterns of the lateral circumflex femoral artery (LCFA), its branches, and perforators and their skin termini, which were compared with the operative findings. RESULTS: Using CE-DISCO, the patterns of the LCFA and its branches were clearly identified in all patients. Four different origins of the LCFA were found among the 60 blood vessels: type I (44/60, 73.3%), type II (6/60, 10.0%), type III (8/60, 13.3%), and type IV (2/60, 3.3%). Owing to a lack of perforators entering the skin, two patients did not undergo ALT flap transplantation. For the remaining 28 patients, the ALT flaps in 26 patients were successfully operated without flap re-selection during the operation, while the remaining two patients underwent other surgical procedures due to the thin diameter of the perforator or injury of the perforator during the operation. The success rate of flap transplantation was 92.8% (26/28). All transplanted flaps exhibited good blood supply and achieved primary healing without infection or delayed healing. CONCLUSION: CE-DISCO imaging can be an effective method for preoperative perforator imaging before ALT flap transplantation.

Combined Effects of 2-Methoxyestradiol (Hypoxia-Inducible Factor 1α Inhibitor) and Dasatinib (A Second-Generation Tyrosine Kinase Inhibitor) on Chronic Myelocytic Leukemia Cells.

Chronic myelocytic leukemia (CML) is a frequently encountered type of leukemia in China. Hypoxia-inducible factor 1 (HIF-1) serves as one of the most important factors of oxygen balance transcription. The activation of this gene mostly marks a poor outlook for cancer patients. To clarify the therapeutic effect of inhibiting this gene on CML, the present study is aimed at exploring the treatment effects of 2-methoxyestradiol (2-ME2), dasatinib alone, and combined both on K-562 cells and the possible mechanism of 2-ME2 in treating the disorder. The levels of HIF-1α, vascular endothelial growth factor (VEGF), and glutamate synthase 1 (GLU1) genes in K-562 cells were affected dose-dependently after 2-ME2 administration. 2-ME2 induced cell apoptosis by downregulating antiapoptotic protein expressions of Bcl-xl and Bcl-2. The therapeutic effect of single 2-ME2 was superior to single dasatinib, and the effect of combined therapy of both drugs produced better effectiveness than either of the single drug. Once the concentration of 2-ME2 exceeded 0.5 µM, downregulated C-myc gene expression could exert roles in anti-CML cell proliferation and inducing apoptosis. Dasatinib might participate in the inhibition of the C-myc pathway during this process whereas its effect remained not clear. Taken together, abnormal high expression of HIF-1α exerted an essential role in CML occurrence and development. Inhibition of this gene could markedly increase cell apoptosis in a dose-dependent fashion. Moreover, 2-ME2 could induce cell apoptosis by downregulating the C-myc gene and exert an apoptotic effect by downregulating Bcl-xl and Bcl-2 which act as antiapoptotic proteins.

The Regulatory Role of MicroRNAs on Phagocytes: A Potential Therapeutic Target for Chronic Diseases.

An effective acute inflammatory response results in the elimination of infectious microorganisms, followed by a smooth transition to resolution and repair. During the inflammatory response, neutrophils play a crucial role in antimicrobial defense as the first cells to reach the site of infection damage. However, if the neutrophils that have performed the bactericidal effect are not removed in time, the inflammatory response will not be able to subside. Anti-inflammatory macrophages are the main scavengers of neutrophils and can promote inflammation towards resolution. MicroRNAs (miRNAs) have great potential as clinical targeted therapy and have attracted much attention in recent years. This paper summarizes the involvement of miRNAs in the process of chronic diseases such as atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus by regulating lipid metabolism, cytokine secretion, inflammatory factor synthesis and tissue repair in two types of cells. This will provide a certain reference for miRNA-targeted treatment of chronic diseases.

Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-based therapy is currently considered to be an effective treatment for NAFLD. The present study aimed to determine whether hUC-MSCs-exosomes have a hepatoprotective effect on NAFLD. We constructed NAFLD rat model by high-fat high-fructose feeding. Liver cells (L-O2) were treated with palmitic acid (PA) to mimic NAFLD model. NAFLD rats and PA-treated L-O2 cells were treated with hUC-MSCs-exosomes, and then we determined the influence of exosomes on liver damage and glucose and lipid metabolism in vivo and in vitro. We found that hUC-MSCs-exosomes exhibited an up-regulation of miR-627-5p. Exosomal miR-627-5p promoted cell viability and repressed apoptosis of PA-treated L-O2 cells. Exosomal miR-627-5p also enhanced the expression of G6Pc, PEPCK, FAS and SREBP-1c and suppressed PPARα expression in PA-treated L-O2 cells. Moreover, miR-627-5p interacted with fat mass and obesity-associated gene (FTO) and inhibited FTO expression in L-O2 cells. MiR-627-5p-enriched exosomes improved glucose and lipid metabolism in L-O2 cells by targeting FTO. In vivo, exosomal miR-627-5p ameliorated insulin tolerance, liver damage, glucose and lipid metabolism and reduced lipid deposition in NAFLD rats. Exosomal miR-627-5p also reduced body weight, liver weight, and liver index (body weight/liver weight) in NAFLD rats. In conclusion, these data demonstrate that HUC-MSCs-derived exosomal miR-627-5p improves glucose and lipid metabolism and alleviate liver damage by repressing FTO expression, thereby ameliorating NAFLD progression. Thus, hUC-MSCs-exosomes may be a potential treatment for NAFLD.

Hydrogen sulfide restores sevoflurane postconditioning mediated cardioprotection in diabetic rats: Role of SIRT1/Nrf2 signaling-modulated mitochondrial dysfunction and oxidative stress.

Diabetic hearts are vulnerable to myocardial ischemia/reperfusion injury (IRI), but are insensitive to sevoflurane postconditioning (SPC), activating peroxiredoxins that confer cardioprotection. Previous studies have demonstrated that hydrogen sulfide (H2 S) can suppress oxidative stress of diabetic rats through increasing the expression of silent information regulator factor 2-related enzyme 1 (SIRT1), but whether cardioprotection by SPC can be restored afterward remains unclear. Diabetic rat was subjected to IRI (30 min of ischemia followed by 120 min reperfusion). Postconditioning treatment with sevoflurane was administered for 15 min upon the onset of reperfusion. The diabetic rats were treated with GYY4137 (H2 S donor) 5 days before the experiment. Myocardial infarct size, mitochondrial structure and function, ATP content, activities of complex I-IV, marker of oxidative stress, SIRT1, nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH Oxidase-2 (Nox-2) protein expression were detected after reperfusion, and cardiac function was evaluated by echocardiography at 24 h after reperfusion. After H2 S activated SIRT1 in the impaired myocardium of diabetic rats, SPC significantly upregulated the expression of Nrf2 and its downstream mediator HO-1, thus reduced the expression of Nox-2. In addition, H2 S remarkably increased cytoplasmic and nuclear SIRT1 which was further enhanced by SPC. Furthermore, H2 S combined with SPC reduced the production of reactive oxygen species, increased the content of ATP, and maintained mitochondrial enzyme activity. Finally, myocardial infarct size and myocardium damage were decreased, and cardiac function was improved. Taken together, our study proved that H2 S could restore SPC-induced cardioprotection in diabetic rats by enhancing and promoting SIRT1/Nrf2 signaling pathway mediated mitochondrial dysfunction and oxidative stress.

Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma.

Natural killer/T cell lymphoma (NKTCL) is an aggressive and heterogeneous entity of non-Hodgkin lymphoma, strongly associated with Epstein-Barr virus (EBV) infection. To identify molecular subtypes of NKTCL based on genomic structural alterations and EBV sequences, we performed multi-omics study on 128 biopsy samples of newly diagnosed NKTCL and defined three prominent subtypes, which differ significantly in cell of origin, EBV gene expression, transcriptional signatures, and responses to asparaginase-based regimens and targeted therapy. Our findings thus identify molecular networks of EBV-associated pathogenesis and suggest potential clinical strategies on NKTCL.

Altered DNA methylation of TRIM13 in diabetic nephropathy suppresses mesangial collagen synthesis by promoting ubiquitination of CHOP.

BACKGROUND: Mesangial collagen synthesis in renal glomeruli contributes to the pathogenesis of diabetic nephropathy (DN) which is one of the most serious complications of diabetes mellitus. However, the underlying mechanism of mesangial collagen synthesis is largely unknown. METHODS: The differential expression of CHOP and TRIM13 which is a well-defined E3 ubiquitin ligase was compared in renal biopsy samples from DN/normal renal tissues, in isolated glomeruli of diabetic/control mice, as well as in high glucose (HG) or TGF-ß1-stimulated renal mesangial cells. Then the relationship between TRIM13 and CHOP was explored using the ubiquitination assay. FINDINGS: We found that the expression of TRIM13 was downregulated in renal biopsies, isolated glomeruli of diabetic mice, and HG/TGF-ß1-stimulated renal mesangial cells, while the expression of CHOP was upregulated. An increased level of TRIM13 promoter methylation contributed to the deregulation of TRIM13 in renal glomeruli of DN. The ubiquitination assay confirmed that TRIM13 promoted ubiquitination and degradation of CHOP. Meanwhile, overexpressing TRIM13 attenuated DN-induced collagen synthesis and restored renal function in vitro and in vivo via downregulating CHOP. INTERPRETATION: Our findings demonstrated that overexpressed TRIM13 suppresses mesangial collagen synthesis in DN by promoting ubiquitination of CHOP, suggesting TRIM13 as a potential therapeutic target in treating DN.

[Effect of miR-214 on Fludarabine Resistance in Chronic Lymphocytic Leukemia].

OBJECTIVE: To investigate effect and mechanism of miR-214 in fludarabine resistance of chronic lympho-cytic leukemia (CLL). METHODS: A total of 10 patients with CLL resistante to fludarabine (Flu) and 10 healthy persons admitted to Hematology Department of our hospital in August 2014 - July 2018 were selected. Expression level of miR-214 in mononuclear cells in patients with CLL and healthy persons were determined by RT-PCR. Primary CLL cells from patients with CLL were divided into normal control group (control group), negative control group (miR-214-NC group) and viral transinfection group (miR-214-ASO group). After 24 h-transfection, CLL cells were cultured with different con-centration of Flu for 48 h, then the cell proliferation and apoptosis were detected, and the levels of down-stream genes and proteins releted with PTEN and PI3K/AKT signialing pathway were determined. RESULTS: The expression level of miR-214 in mononuclear cells of CLL patients significantly increased in comparison with healthy persons(P<0.05); the expression level of miR-214 in miR-214-ASO group significantly decreased (P<0.05); Absorbance in control group at Flu concentration of 3, 10 and 30 µmol/L was significantly decreased (P<0.05). Apoptosis rate in miR-214-ASO group at Flu concentration of 10 mmol/L significantly increased (P<0.05). At Flu concentration of 10 mmol/L, mRNA levels PTEN and BAD in miR-214-ASO group significantly increased (P<0.05), but mRNA levels of MDM2 and NF-κB significantly decreased (P<0.05). At Flu concentration of 10 mmol/L, protein levels of PTEN and p-BAD in miR-214-ASO group significantly increased (P<0.05), but protein levels of MDM2 and NF-κB significantly decreased (P<0.05). CONCLUSION: Inhibition of miR-214 can enhance the sensitivity of drug-resistant CLL cells to fludarabine, which may be raleted with the promotion of cell apotosis and regulation of down-stream molecules expression of PTEN/AKT signaling pathway.

Relationship of WNT4 Gene with the Risk of Epithelial Ovarian Cancer: A Han Chinese Population-Based Association Study.

OBJECTIVE: In China, epithelial ovarian cancer (EOC) patients account for the majority of ovarian cancer patients. The pathogenesis of EOC, one of the most lethal gynecological malignancies, remains unclear. Recently, the role of WNT4 in gynecological disease and tumor development was reported, and a suspicious association of WNT4 with EOC was identified in Europeans. However, the contributions of the WNT4 gene to EOC and the underlying molecular mechanisms remains largely unknown. To determine whether the WNT4 gene is associated with EOC, this study investigated polymorphisms of the WNT4 gene in Han Chinese individuals. MATERIALS AND METHODS: We designed a case/control study with 707 EOC patients and 1563 unrelated healthy controls of Han Chinese descent. A total of eight tag single-nucleotide polymorphisms (SNPs) were genotyped successfully, and both single SNP and haplotype analyses were performed to detect the potential association of variations in the WNT4 gene with EOC. RESULTS: The SNP rs56318008 was found to be strongly associated with EOC risk. In the serous EOC subgroup, individuals harboring the T allele of rs56318008 exhibited a higher risk of EOC than individuals harboring the C allele. Moreover, the odds ratios and 95% confidence intervals revealed an increased risk of EOC in individuals with the T allele of the SNP, and haplotypic analyses confirmed the results, showing a similar pattern. CONCLUSION: Our results show that the WNT4 gene is associated with EOC risk, indicating that this gene may be a potential genetic risk factor for developing EOC.

[Influence of Chromosome Abnormality on Therapeutic Efficacy and Prognosis of Newly Diagnosed Multiple Myeloma Treated with Bortezomib].

OBJECTIVE: To explore the influence of chromosome abnormality on therapeutic efficacy and prognosis of patients with newly diagnosed multiple myeloma(MM) treated with bortezomib. METHODS: The clinical data of 152 patients with newly diagnosed MM were collected from January 2008 to December 2011. All patients received bortezo-mib-based chemotherapy and the therapeutic efficacy were investigated for 4 cycles later. The R banding and DNA probe were used to analyze the chromosome and gene (RB1 deletion, D13S319 deletion, P53 deletion, IgH rearrangement and 1q21 amplification) of chromosome specimens. Moreover, the therapeutic efficacy and long-term survival data were analyzed among the patients with different types of chromosomal abnormality. The Kaplan-Meier was applied to analyze survival, and COX risk proportional model was used for multivariate analysis. RESULTS: Among 152 patients with MM, there were 47 cases(30.92%) of abnormal karyotype, 43 cases(28.29%) of abnormal RB1,49 cases (32.24%) of abnormal D13S319, 30 cases (19.74%) of abnormal P53, 58 cases (38.16%) of abnormal IgH and 33 cases (21.71%) of abnormal chromosome 1q21. All the patients were evaluable for the therapeutic efficacy, including 24 CR, 54 nCR, 21 PR, 14 MR and 39 PD with response rate of 74.34% and remission rate of 50.66%. Compared with normal controls, the response and remission rate were lower than that in the patients with abnormal karyotype of D13S319, P53 or IgH, and remission rate was lower in the patients with RB1 or 1q21 (P<0.05). All the patients were followd-up (median: 52.0 months, range: 22-72 months), but median overall survival(OS) was not yet reached at the end of the follow-up. The median OS was in the patients with different chromosome versus the normal subjects (P<0.05). The chromosome abnormality was found to affect the prognosis of MM by COX multivariate analysis. In regard to the normal subjects, the risk for poor prognosis increased by 1.177, 2.639, 6.552, 3.124, 2.045 and 7.264 fold in the patients with abnormal Karyotype of RB1, D13S319, P53, IgH and 1q21, respectively. CONCLUSION: The abnormality of chromosome can influence the efficacy and prognosis of newly diagnosed MM patients treated with bortezomib. The detection of chromosomal abnormalities has a certain reference value for the treatment of primary MM.

Proteomic Profiling of Iron Overload-Induced Human Hepatic Cells Reveals Activation of TLR2-Mediated Inflammatory Response.

BACKGROUND: Hepatic iron overload is common in patients who have undergone hematopoietic cell transplantation (HCT) and may predispose to peri- and post-HCT toxicity. To better reveal more molecules that might be involved in iron overload-induced liver injury, we utilized proteomics to investigate differentially expressed proteins in iron overload-induced hepatocytes vs. untreated hepatocytes. METHODS AND RESULTS: HH4 hepatocytes were exposed to ferric ammonium citrate (FAC) to establish an in vitro iron overload model. Differentially expressed proteins initiated by the iron overload were studied by two-dimensional liquid chromatography tandem mass spectrometry (2D-LC-MS) analysis. We identified 93 proteins whose quantity statistically significantly changes under excess hepatocyte iron conditions. Gene Ontology (GO) analysis showed that these differentially expressed proteins in HH4 cells are involved in various biological process including endocytosis, response to wounding, di-, trivalent inorganic cation homeostasis, inflammatory response, positive regulation of cytokine production, and etc. Meanwhile, proteomics data revealed protein level of TLR2 and IL6ST significantly increased 7 times and 2.9 times, respectively, in iron overloaded HH4 cells. Our subsequent experiments detected that FAC-treated HH4 cells can activate IL6 expression through TLR2-mediated inflammatory responses via the NF-κB pathway. CONCLUSIONS: In this study, we demonstrated that iron overload induced hepatocytes triggering TLR2-mediated inflammatory response via NF-κB signaling pathway in HH4 cells.

Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent.

Mammalian target of rapamycin (mTOR) as a potential drug target for treatment of acute myeloid leukemia (AML). Here, we investigated the potential anti-leukemic activity by WYE-687, a potent mTOR kinase inhibitor. We demonstrated that WYE-687 potently inhibited survival and proliferation of established (HL-60, U937, AML-193 and THP-1 lines) and human AML progenitor cells. Yet, same WYE-687 treatment was non-cytotoxic to the primary peripheral blood mononuclear leukocytes (PBMCs) isolated from healthy donors. WYE-687 induced caspase-dependent apoptotic death in above AML cells/progenitor cells. On the other hand, the pan-caspase inhibitor (Z-VAD-FMK), the caspase-3 specific inhibitor (Z-DEVD-FMK) or the caspase-9 specific inhibitor (z-LEHD-fmk) attenuated WYE-687-induced cytotoxicity. At the molecular level, WYE-687 concurrently inhibited activation of mTORC1 (p70S6K1 and S6 phosphorylations) and mTORC2 (AKT Ser-473 and FoxO1/3a phosphorylations), whiling downregulating mTORC1/2-regulated genes (Bcl-xL and hypoxia-inducible factor 1/2α) in both HL-60/U937 cells and human AML progenitor cells. In vivo, oral administration of WYE-687 potently inhibited U937 leukemic xenograft tumor growth in severe combined immunodeficient (SCID) mice, without causing significant toxicities. In summary, our results demonstrate that targeting mTORC1/2 by WYE-687 leads to potent antitumor activity in preclinical models of AML.

Replication analysis confirms the association of several variants with acute myeloid leukemia in Chinese population.

PURPOSE: Two genome-wide association studies (GWASs) have identified several new acute leukemia susceptibility loci in populations of European descent. However, the roles of these loci in the development of acute leukemia in other populations are largely unknown. METHODS: We genotyped 16 single-nucleotide polymorphisms selected from published GWASs in an independent case-control study with a total of 545 acute myeloid leukemia (AML) cases and 1034 cancer-free controls in a Chinese population. Multivariate logistic regression was used to analyze the associations between these variants and AML risk. RESULTS: We found that with the similar effect to GWASs, risk alleles of rs2191566, rs9290663, rs11155133, rs2239633, rs10821936, and rs2242041 significantly increased the risk of AML in at least one genetic model [odds ratios (ORs) range from 1.26 to 4.34, P values range from <0.001 to 0.043]. However, the variant T allele of rs10873876 decreased the AML risk, which was in the opposite effect direction (OR 0.62, P < 0.001 in additive model). Besides, we found significant multiplicative interaction between rs9290663 and age (≤45 years old and >45 years old; P = 0.009). CONCLUSION: Our results indicated that genetic variants associated with acute leukemia risk in European populations may also play important roles in AML development in Chinese population.

Ganoderma lucidum polysaccharide exerts anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

In this study, we investigated the anti-tumor activity both in vitro and in vivo of a polysaccharide obtained from Ganoderma lucidum on HL-60 acute myeloid leukemia cells, and focused on its targeting effect on mitogen-activated protein kinase (MAPK) pathways. It was found by the methods such as western blot and flow cytometry (FCM), that G. lucidum polysaccharide (GLP) blocked the extracellular signal-regulated kinase/MAPK signaling pathway, simultaneously activated p38 and JNK MAPK pathways, and therefore regulated their downstream genes and proteins, including p53, c-myc, c-fos, c-jun, Bcl-2, Bax, cleaved caspase-3 and cyclin D1. As a result, cycle arrest and apoptosis of HL-60 cells were induced. Therefore, GLP exerted anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

Uterine artery embolization for hemorrhage resulting from second-trimester abortion in women with scarred uterus: report of two cases.

This study was conducted to investigate the effect of uterine artery embolization for the treatment of hemorrhage following second-trimester labor induction for women with scarred uterus. Two cases of second-trimester abortion were retrospectively reviewed, both of which had a history of caesarean delivery and were complicated by gestational anemia. One was at 18 weeks' gestation and presented with persistent vaginal bleeding for two months resulting in relatively large area of blood clot in uterine cavity. The other was at 25 weeks' gestation with partial hydatidiform mole and presented with intermittent vaginal bleeding. Both patients presented with continuous and heavy vaginal bleeding after oral administration of mifepristone for labor induction, with one cervix left unopened, while the other cervix 3 cm left dilatation, yet felt obstructed by pregnant tissue. Both patients were immediately treated with uterine artery embolization (UAE). Both patients presented with alleviated hemorrhage and regular uterine contraction after UAE, followed by smooth induction of labor. No hemorrhage occurred since then during the follow-up. The results suggest that UAE is safe and effective for the treatment of massive hemorrhage of second-trimester abortion in women with scarred uterus. It can reduce time period of labor induction and alleviate hemorrhage, which not only rescues patients but also avoids cesarean sections and retains fertility for the pregnant.

Effect of Pin1 inhibitor juglone on proliferation, migration and angiogenic ability of breast cancer cell line MCF7Adr.

This study aimed to evaluate the effects of Pin1 inhibitor Juglone on proliferation, migration and the angiogenic ability of breast cancer cell line MCF7Adr. MCF7Adr cells were cultured and separately treated with Pin1 inhibitor Juglone (treatment group) and DMEM without drug (control group). The cell cycle was examined by flow cytometry. Cell migration was measured by wound-healing assay. Cyclin E protein content was detected by Western blotting. The angiogenesis factor vascular endothelial growth factor (VEGF) in cell media was determined by enzyme linked immunosorbent assay. The results showed that the percentage of cells in G2/M phase in treatment group was significantly higher than that in control group (25.5% vs. 10.1%, P<0.05), and that in G0/G1 phase and S stage in treatment group was significantly lower than that in control group (40.5% vs. 48.2%, and 33.7% vs. 41.7%, P<0.05). Cyclin E protein content in treatment group was significantly lower than that in control group (39.2 ± 7.4 vs. 100 ± 23.1, P<0.05). (A0-A24)/A0 value in treatment group was significantly lower than that in control group (23.9 ± 3.8 vs. 100 ± 14.4, P<0.05). VEGF-A, -B, and -C contents in cell media of treatment group were significantly lower than those in control group (P<0.05). It was suggested that Pin1 inhibitor Juglone can effectively inhibit the proliferation, migration and the angiogenic ability of MCF7Adr cells, and can be used as an alternative drug therapy for breast cancer.