Endoscopic submucosal dissection for early cancers or precancerous lesions of the upper GI tract in cirrhotic patients with esophagogastric varices: 10-year experience from a large tertiary center in China.

BACKGROUND AND AIMS: Treatment strategies for early cancers or precancerous lesions of the upper GI tract in patients with cirrhosis and esophagogastric varices (EGVs) are complicated and risky. The aim of this study was to assess the efficacy and safety of endoscopic submucosal dissection (ESD) in the treatment of such patients and explore optimal treatment strategies. METHODS: We retrospectively enrolled 15 patients with cirrhosis and EGV who underwent ESD for early cancers or precancerous lesions of the upper GI tract from January 2012 to December 2021 at our center. Clinical features, endoscopic findings, treatment methods, adverse events, and follow-up data were analyzed. RESULTS: Of the 15 patients, 1 had a platelet count <30 × 1000/mm3. Five were untreated for EGV, 1 was treated after ESD, 6 were treated before ESD, 1 was treated before and during ESD, and 2 were treated during ESD. The R0 resection rate was 100%. Of the 16 mucosal lesions, 15 were endoscopic resection bleeding (ERB)-0 or ERB-c1, and 1 was ERB-c2. No patient experienced deterioration in liver function. The only adverse events were fever in 2 patients and postoperative bleeding in 2 patients. During a median follow-up of 27 months, 1 patient's esophageal high-grade dysplasia recurred at 19 months. No death resulted from the ESD procedure, liver function injury, or GI tumor itself. CONCLUSIONS: ESD is an effective and safe treatment for early cancers or precancerous lesions of the upper GI tract in patients with cirrhosis and EGV. The incidence of severe adverse events is very low due to the development of individualized clinical treatment strategies.

Intrauterine inflammation induced white matter injury protection by fibrinogen-like protein 2 deficiency in perinatal mice.

BACKGROUND: White matter injury (WMI) induced by intrauterine inflammation can cause adverse neurological outcomes. Fibrinogen-like protein 2 (FGL2)/fibroleukin is an important trigger of inflammatory responses and is involved in some cerebral diseases. However, the role of FGL2 in intrauterine inflammation-induced WMI remains unclear. METHODS: Lipopolysaccharide (LPS) was intraperitoneally injected into wild-type and FGL2 knockout mice to induce intrauterine inflammation. Body weight and brain weight of offspring were monitored. Major basic protein (MBP) expression was evaluated to demonstrate the myelination of offspring. To investigate the regulatory mechanism of FGL2, cytokine expression, microglial polarization, and the activation of mitogen-activated protein kinase (MAPK) signaling pathway in the offspring were analyzed. RESULTS: Upon LPS exposure, FGL2 knockout offspring showed a significant increase in body weight loss. MBP reduction induced by LPS was prevented in FGL2 knockout offspring. Expression levels of proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α, and M1 marker CD86 were suppressed, while the expression levels of anti-inflammatory cytokines IL-10 and M2 marker CD206 were increased. FGL2 deficiency significantly inhibited the phosphorylation of p38MAPK and c-Jun N-terminal kinase (JNK) protein. CONCLUSIONS: FGL2 deficiency can ameliorate WMI induced by intrauterine inflammation, reducing inflammatory cascade and improving hypomyelination, through the regulation of microglial polarization and MAPK signaling pathways. IMPACT: Intrauterine inflammation induces WMI leading to severe neurological sequelae. FGL2 plays an important role in the progression of WMI induced by intrauterine inflammation. FGL2 deficiency can protect against WMI by inhibiting p38 MAPK and JNK phosphorylation, regulating microglia polarization, and reducing inflammation response. FGL2 could be a novel molecular target for protecting against WMI induced by intrauterine inflammation.

Effect of high-fat diet for rats at different stages on glucose and lipid metabolism in offspring and related mechanisms. / å¤§é¼ ä¸åŒæ—¶æœŸé«˜è„‚é¥®é£Ÿå¯¹å­ä»£ç³–è„‚ä»£è°¢çš„å½±å“åŠæœºåˆ¶ç ”ç©¶.

OBJECTIVES: To study the effect of high-fat diet for maternal Sprague-Dawley rats at different stages on glucose and lipid metabolism in offspring and related mechanisms. METHODS: According to the diet before pregnancy and during pregnancy and lactation, maternal rats were randomly divided into four groups (n=9 each): CC (control diet before pregnancy and during pregnancy and lactation), HC (high-fat diet before pregnancy and control diet during pregnancy and lactation), CH (control diet before pregnancy and high-fat diet during pregnancy and lactation), and HH (high-fat diet before pregnancy and during pregnancy and lactation), and all offspring rats were given control diet after weaning. The body weight of maternal rats was recorded before and during pregnancy. Male offspring rats were selected from each group at the juvenile stage (3-week old) and the adult stage (12-week old) to measure the levels of fasting blood glucose (FBG) and fasting insulin (FINS) and the levels of triglyceride (TG) and total cholesterol (TC) in the liver. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated, and the area under the curve (AUC) was calculated for glucose tolerance test (GTT) and insulin tolerance test (ITT). Lipid deposition in the liver was observed, and the mRNA and protein expression levels of the key genes in glucose and lipid metabolism (IR, IRS, and AKT), FASN, SREBP1c, and PPARα in the liver were also measured. RESULTS: Compared with the control diet groups (CC and CH groups), the groups with high-fat diet before pregnancy (HC and HH groups) had a significant increase in body weight (P<0.001). Compared with the CC group, the HC, CH, and HH groups had a significantly greater increase in body weight (P<0.001). Compared with the CC group, the HC, CH, and HH groups had significant increases in body weight, the levels of TG and TC in the liver, and the mRNA and protein expression levels of FASN, SREBP1c, and PPARα in the offspring rats at week 3 after birth (P<0.05), as well as a significant increase in lipid deposition in the liver, with the most significant increase of the parameters in the HH group. Compared with the CC group, the HH group had significant increases in the levels of FBG and FINS, HOMA-IR index, GTT-AUC, ITT-AUC, and the protein expression level of p-IRS in the liver and significant reductions in the mRNA and protein expression levels of IR and IRS in the liver in the offspring rats at week 3 after birth (P<0.05). Compared with the CC group, the HC, CH, and HH groups had significant increases in body weight, the levels of FBG and FINS, HOMA-IR index, GTT-AUC, ITT-AUC, the levels of TG and TC in the liver, protein expression level of p-IRS in the liver, and the mRNA and protein expression levels of FASN, SREBP1c, and PPARα in the offspring rats at week 12 after birth (P<0.05), as well as a significant increase in lipid deposition in the liver, with the most increase of the parameters in the HH group. Compared with the CC group, the HC, CH, and HH groups had significant reductions in the mRNA expression levels of IR, IRS, and AKT and the protein expression levels of IR, IRS, and p-AKT in the offspring rats at week 12 after birth (P<0.05). There were no significant differences in the levels of glucose and lipid metabolism between the HC and CH groups at various stages (P>0.05). CONCLUSIONS: High-fat diet for rats at different stages before and after pregnancy has different effects on glucose and lipid metabolism of offspring rats, and high-fat diet before pregnancy and during pregnancy and lactation has the greatest effect. The effect of high-fat diet on glucose and lipid metabolism of offspring rats is considered associated with the changes in the expression of genes involved in glucose and lipid metabolism.

The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes.

Although cytarabine has been widely considered as one of the chemotherapy drugs for high-risk myelodysplastic syndromes (MDS), the overall response rate is only approximately 20-30%. Nuclear factor erythroid 2-related factor 2 (NRF2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. However, it is not yet known whether NRF2 can be used as a prognostic biomarker in MDS, or whether elevated NRF2 levels are associated with cytarabine resistance. Here, we found that NRF2 expression levels in bone marrow from high-risk patients exceeded that of low-risk MDS patients. Importantly, high NRF2 levels are correlated with inferior outcomes in MDS patients (n=137). Downregulation of NRF2 by the inhibitor Luteolin, or lentiviral shRNA knockdown, enhanced the chemotherapeutic efficacy of cytarabine, while MDS cells treated by NRF2 agonist Sulforaphane showed increased resistance to cytarabine. More importantly, pharmacological inhibition of NRF2 could sensitize primary high-risk MDS cells to cytarabine treatment. Mechanistically, downregulation of dual specificity protein phosphatase 1, an NRF2 direct target gene, could abrogate cytarabine resistance in NRF2 elevated MDS cells. Silencing NRF2 or dual specificity protein phosphatase 1 also significantly sensitized cytarabine treatment and inhibited tumors in MDS cells transplanted mouse models in vivo Our study suggests that targeting NRF2 in combination with conventional chemotherapy could pave the way for future therapy for high-risk MDS.

Photosynthetic response of Chlamydomonas reinhardtii and Chlamydomonas sp. 1710 to zinc toxicity.

Zinc (Zn) is an essential trace element but can lead to water contamination and ecological deterioration when present in excessive amounts. Therefore, investigating the photosynthetic response of microalgae to Zn stress is of great significance. In this study, we assessed the photosynthetic responses of neutrophilic Chlamydomonas reinhardtii and acidophilic Chlamydomonas sp. 1710 to Zn exposure for 96 h. The specific growth rate (µ), chlorophyll-a (Chl-a) content, and chlorophyll fluorescence parameters were determined. The results demonstrated that Chlamydomonas sp. 1710 was much more tolerant to Zn than C. reinhardtii, with the half-maximal inhibitory concentration (IC50) values of 225.4 mg/L and 23.4 mg/L, respectively. The µ and Chl-a content of C. reinhardtii decreased in the presence of 15 mg/L Zn, whereas those of Chlamydomonas sp. 1710 were unaffected by as high as 100 mg/L Zn. Chlorophyll fluorescence parameters indicated that the regulation of energy dissipation, including non-photochemical quenching, played a crucial role in Zn stress resistance for both Chlamydomonas strains. However, in the case of C. reinhardtii, non-photochemical quenching was inhibited by 5 mg/L Zn in the first 48 h, whereas for Chlamydomonas sp. 1710, it remained unaffected under 100 mg/L Zn. Chlamydomonas sp. 1710 also exhibited a 20 times stronger capacity for regulating the electron transfer rate than C. reinhardtii under Zn stress. The light energy utilization efficiency (α) of Chlamydomonas sp. 1710 had the most highly non-linear correlation with µ, indicating the energy utilization and regulation process of Chlamydomonas sp. 1710 was well protected under Zn stress. Collectively, our findings demonstrate that the photosystem of Chlamydomonas sp. 1710 is much more resilient and tolerant than that of C. reinhardtii under Zn stress.

FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress.

Introduction: The impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined. Methods: Lipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying. Results: Upon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs. Conclusion: Our findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

Stem Cells in the Myelodysplastic Syndromes.

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation.

Clinical and Functional Characterization of a Novel Mutation in AVPR2 Causing Nephrogenic Diabetes Insipidus in a Four-Generation Chinese Family.

Background: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease that is caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2). Functional analysis of the mutated receptor is necessary to verify the impact of the mutation on receptor function and suggest some possible therapeutic strategies for specific functional defects. Methods: Family history and clinical information were collected. Whole-exome sequencing and sanger sequencing were performed to determine the potential genetic cause of diabetes insipidus. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Bioinformatic analysis was performed to predict the function of the identified variation. Moreover, wild-type and mutated AVPR2 vectors were constructed and transfection to HEK-293T cells. Immunofluorescence experiments were performed to investigate the expression and localization of the mutated protein and cAMP parameter assays were used to measure its activity in response to AVP. Results: The heights of the adult members affected with polyuria and polydipsia were normal, but all affected children had growth retardation. Next-generation sequencing identified a novel mutation in AVPR2 gene (c.530T > A) in this family. Bioinformatic analysis indicated that the mutation in AVPR2 changed the hydropathic characteristic of the protein and was probably deleterious. Although immunofluorescence showed that the mutated AVPR2 was normally expressed in the cell surface, the intracellular cAMP concentration stimulated by AVP was significantly lower in cells transfected with mutated AVPR2 than cells transfected with wild-type AVPR2. Based on the ACMG criteria, the novel c.530T > A variant of the AVPR2 gene was likely pathogenic and the affected family members were diagnosed as CNDI. After the confirmation of the diagnosis, the proband was treated with compound amiloride hydrochloride and rhGH, the symptoms of polyuria, polydipsia and growth retardation were all improved. Conclusion: These findings suggested that the novel mutation in AVPR2 (c.530T > A) was a true disease-causing variant with mild effects, which could be classified as a type III mutant receptor. Moreover, investigations of the function of growth hormone axis could be important for the pediatric CNDI patients with extreme short stature, and rhGH treatment might improve the final adult heights in these patients.

Anti-androgenetic alopecia effect of policosanol from Chinese wax by regulating abnormal hormone levels to suppress premature hair follicle entry into the regression phase.

Previously, we have demonstrated that policosanol from Chinese wax suppressed testosterone(T)-induced alopecia in mice. However, the underlying mechanism remained to be determined. Herein, we investigated the mechanism of policosanol against androgenetic alopecia (AGA). AGA was induced in Kunming mice by subcutaneous administration of testosterone propionate for 60 d. Policosanol (0.5 %, 1% or 2%) was applied topically on the back of mice. Finasteride (2%) was applied topically as a positive control. The serum T and estradiol (E2) concentrations were determined by ELISA after 28 and 60 days of treatment. The cutaneous expression or activity of key mediators of hair growth, such as alkaline phosphatase (ALP), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), was measured. MTS assay was performed to evaluate cell proliferation in cultured human dermal papilla cells (DPCs) treated with dihydrotestosterone (DHT). Western blotting was performed to evaluate the protein expression of Bax, Bcl2, TGF-ß2, caspase-9, and caspase-3. We found lower T and T/E2 ratio in mice treated with policosanol than in the model group. Policosanol suppressed premature hair follicle entry into the regression phase, as shown by improving VEGF and EGF expression and ALP activity. The MTS assay showed that policosanol markedly inhibited the apoptosis of DHT-treated DPCs. Western blotting showed that policosanol significantly reduced the protein expression of TGF-ß2, cleaved caspese-9, cleaved caspase-3, and Bax, and increased that of Bcl2. The optimal effect was obtained with 12.50 g/mL policosanol. In conclusion, policosanol prevents androgenetic alopecia by regulating hormone levels and suppressing premature hair follicle entry into the regression phase.

Tumor Microenvironment-Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy.

Natural killer (NK) cells and T cells are key effectors of antitumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g., RSPO3) is associated with favorable prognosis and positively correlates with gene signatures of both NK cells and T cells. Although endothelial cells and cancer-associated fibroblasts comprise the R-spondin 3-producing cells, NK cells and T cells correspondingly express the R-spondin 3 receptor LGR6 within the tumor microenvironment (TME). Exogenous expression or intratumor injection of R-spondin 3 in tumors enhanced the infiltration and function of cytotoxic effector cells, which led to tumor regression. NK cells and CD8+ T cells independently and cooperatively contributed to R-spondin 3-induced control of distinct tumor types. The effect of R-spondin 3 was mediated in part through upregulation of MYC and ribosomal biogenesis. Importantly, R-spondin 3 expression enhanced tumor sensitivity to anti-PD-1 therapy, thereby highlighting new therapeutic avenues. SIGNIFICANCE: Our study identifies novel targets in enhancing antitumor immunity and sensitizing immune checkpoint inhibition, which provides a rationale for developing new immunotherapies against cancers. It also offers mechanistic insights on Wnt signaling-mediated modulation of anticancer immunity in the TME and implications for a putative R-spondin-LGR6 axis in regulating NK-cell biology. This article is highlighted in the In This Issue feature, p. 2945.

Identification and characterization of the MADS-box genes highly expressed in the laticifer cells of Hevea brasiliensis.

MADS-box transcription factors possess many functions in plant reproduction and development. However, few MADS-box genes related to secondary metabolites regulation have been identified. In Hevea brasiliensis, natural rubber is a representative cis-polyisoprenoids in secondary metabolism which occurs in the rubber laticifer cells, the molecular regulation basis of natural rubber biosynthesis is not clear. Here, a total of 24 MADS-box genes including 4 type I MADS-box genes and 20 type II MADS-box genes were identified in the transcriptome of rubber tree latex. The phylogenetic analysis was performed to clarify the evolutionary relationships of all the 24 rubber tree MADS-box proteins with MADS-box transcription factors from Arabidopsis thaliana and Oryza sativa. Four type I MADS-box genes were subdivided into Mα (3 genes) and Mß (1 gene). Twenty type II MADS-box genes were subclassified into MIKC* (8 genes) and MIKCc (12 genes). Eight MADS-box genes (HblMADS3, 5, 6, 7, 9, 13, 23, 24) were predominant expression in laticifers. ABA up-regulated the expression of HblMADS9, and the expression of HblMADS3, HblMADS5, HblMADS24 were up-regulated by MeJA. The function of HblMADS24 was elucidated. HblMADS24 bound HbFPS1 promoter in yeast and HblMADS24 activated HbFPS1 promoter in tobacco plants. Moreover, we proposed that HblMADS24 is a transcription activator of HbFPS1 which taking part in natural rubber biosynthesis.

Decreased Circulating Levels of Asprosin in Obese Children.

BACKGROUND: Circulating asprosin is a newly discovered adipokine that triggers the release of hepatic glucose stores and increases appetite. Asprosin levels are elevated in adult obese men as well as in mice, and reductions in asprosin protect against the hyperinsulinism associated with metabolic syndrome in mice with diet-induced obesity, which indicates a potential therapeutic role of asprosin in obesity and type 2 diabetes. OBJECTIVES: Few data on asprosin in children are available, which is why this study aimed to assess concentrations of fasting asprosin, as well as its relationship to parameters of glucose and lipid metabolism, in children. METHODS: Data on clinical and metabolic parameters were collected from 40 healthy normal-weight and 47 obese children. Circulating asprosin levels were measured using an ELISA. RESULTS: The concentrations of fasting asprosin were lower in the obese children (9.24 ± 4.11 ng/mL) than in the normal-weight controls (12.33 ± 4.18 ng/mL, p < 0.001). When comparing the two groups by sex, both the boys and the girls showed similar trends. In within-group comparison, the asprosin levels were lower in boys than in girls only in the obese group (8.13 ± 4.10 vs. 10.61 ± 3.78 ng/mL, p = 0.013) but not in the control group. Interestingly, asprosin was correlated with ALT after adjusting for age and sex in all participants; in boys, asprosin was correlated with BMI, HOMA-IR, insulin, and HDL after adjusting for age. CONCLUSIONS: Concentrations of asprosin were significantly lower in obese children than in normal-weight children, and there was a gender difference in asprosin concentration. Our results suggest a complex role for asprosin in energy metabolism.

SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints.

SETD2, an epigenetic tumor suppressor, is frequently mutated in MLL-rearranged (MLLr) leukemia and relapsed acute leukemia (AL). To clarify the impact of SETD2 mutations on chemotherapy sensitivity in MLLr leukemia, two loss-of-function (LOF) Setd2-mutant alleles (Setd2F2478L/WT or Setd2Ex6-KO/WT) were generated and introduced, respectively, to the Mll-Af9 knock-in leukemia mouse model. Both alleles cooperated with Mll-Af9 to accelerate leukemia development that resulted in resistance to standard Cytarabine-based chemotherapy. Mechanistically, Setd2-mutant leukemic cells showed downregulated signaling related to cell cycle progression, S, and G2/M checkpoint regulation. Thus, after Cytarabine treatment, Setd2-mutant leukemic cells exit from the S phase and progress to the G2/M phase. Importantly, S and G2/M cell cycle checkpoint inhibition could resensitize the Mll-Af9/Setd2 double-mutant cells to standard chemotherapy by causing DNA replication collapse, mitotic catastrophe, and increased cell death. These findings demonstrate that LOF SETD2 mutations confer chemoresistance on AL to DNA-damaging treatment by S and G2/M checkpoint defects. The combination of S and G2/M checkpoint inhibition with chemotherapy can be explored as a promising therapeutic strategy by exploiting their unique vulnerability and resensitizing chemoresistant AL with SETD2 or SETD2-like epigenetic mutations.

Characterization of fibroblast growth factor 1 in obese children and adolescents

Background: Fibroblast growth factor 1 (FGF1) can regulate glucose and lipid metabolism in obese mice. Serum FGF1 has increased in type 2 diabetes mellitus adults and correlated with BMI. This study aimed to indicate conventional weight loss effects on FGF1 in obese children and adolescents. Materials and Methods: Clinical and metabolic parameters of 88 lean and obese individuals (ages 5­15 years) and 39 obese individuals followed with 6 months of lifestyle intervention were collected. Serum FGF1 levels were detected through enzyme-linked immunosorbent assays. Results: FGF1 levels were increased in obese individuals. Serum FGF1 levels were significantly correlated with BMI and waist circumferences (r = 0.377, P = 0.012; r = 0.301, P = 0.047, respectively). Multivariate stepwise linear regression analyses showed that FGF1 levels were significantly correlated with HbA1c and HOMA-IR (ß = 0.371, P = 0.008; ß = 0.323, P = 0.021, respectively). Weight loss (2.3 ± 0.1 kg) was accompanied by a significant reduction of circulating FGF1 levels (7.2 ± 0.4 pg/mL). Changes in FGF1 were significantly correlated with changes in fasting glucose, HOMA-IR and low-density lipoprotein cholesterol (ß = 0.277, P = 0.020; ß = 0.474, P < 0.001; ß = 0.320, P = 0.008, respectively). Conclusion: FGF1 levels were increased in obese individuals. Serum FGF1 levels were significantly correlated with BMI and waist circumferences (r = 0.377, P = 0.012; r = 0.301, P = 0.047, respectively). Multivariate stepwise linear regression analyses showed that FGF1 levels were significantly correlated with HbA1c and HOMA-IR (ß = 0.371, P = 0.008; ß = 0.323, P = 0.021, respectively). Weight loss (2.3 ± 0.1 kg) was accompanied by a significant reduction of circulating FGF1 levels (7.2 ± 0.4 pg/mL). Changes in FGF1 were significantly correlated with changes in fasting glucose, HOMA-IR and low-density lipoprotein cholesterol (ß = 0.277, P = 0.020; ß = 0.474, P < 0.001; ß = 0.320, P = 0.008, respectively).

Characterization of Wnt1-inducible Signaling Pathway Protein-1 in Obese Children and Adolescents.

Wnt1-inducible signaling pathway protein-1 (WISP1), a member of the CCN family, is increasingly being recognized as a potential target for obesity and type 2 diabetes mellitus. Recent studies have shown that WISP1 can regulate low-grade inflammation in obese mice, and circulating WISP1 levels are associated with obesity and type 2 diabetes mellitus in adults. Herein, we measured serum WISP1 levels in obese youth and explored its relationships with pro-inflammatory cytokine interleukin 18 (IL-18) and other metabolic indexes. Totally, 44 normal-weight and 44 obese children and adolescents were enrolled. Physical and laboratory data were recorded, and then serum levels of WISP1 and IL-18 were determined by enzyme-linked immunosorbent assays. Results showed that serum levels of WISP1 were significantly higher in obese children and adolescents than in normal-weight healthy controls (1735.44±15.29 vs. 1364.08±18.69 pg/mL). WISP1 levels were significantly positively correlated with body mass index (BMI) and BMI z-score (r=0.392, P=0.008; r=0.474, P=0.001, respectively) in obese group; circulating IL-18 was increased in obese individuals (1229.06±29.42 vs. 295.87±13.30 pg/mL). Circulating WISP1 levels were significantly correlated with IL-18 (r=0.542, P<0.001), adiponectin (r=0.585, P<0.001) and leptin (r=0.592, P<0.001). The multivariate stepwise regression analysis showed that higher IL-18 levels represented the main determinant of increased WISP1 levels after adjusting for BMI, waist circumference, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and HbA1c in obese individuals (ß=0.542, P=0.000). WISP1 can be involved in glucose/lipid metabolism in obese youth, which may be modulated by IL-18. Increased WISP1 levels may be a risk factor of obesity and insulin resistance, and WISP1 has a potential therapeutic effect on insulin resistance in obese children and adolescents.

Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia.

Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.

Dihydropyrimidine dehydrogenase predicts survival and response to interferon-α in hepatocellular carcinoma.

Metastasis and recurrence contribute to poor prognosis of hepatocellular carcinoma (HCC). Recently, we reported that interferon-α (IFN-α) can suppress metastasis of HCC; however, the underlying mechanism has not been fully described. In this study, we demonstrated that expression of dihydropyrimidine dehydrogenase (DPYD), a pyrimidine catabolic enzyme, was dose-dependently downregulated by IFN-α in HCC tissues from nude mice. Notably, DPYD expression was found to be significantly increased in HCC cell lines with higher metastatic potentials compared with their controls. Moreover, upregulation of DPYD in HCC cells could promote in vitro migration, invasion, and in vivo lung metastasis, and inducing changes characteristic of epithelial-mesenchymal transition (EMT). In contrast, knockdown of DPYD inhibited these processes. Mechanistically, DPYD functioned as a positive regulator of EMT in HCC by targeting the p38/NF-κB/Snail1 pathway. Clinically, tissue microarray analysis showed that high DPYD expression was positively associated with aggressive tumor characteristics, including larger tumor size, tumor recurrence, and advanced tumor node metastasis (TNM) stage, and independently correlated with poorer overall survival times after curative resection. HCC patients with low DPYD expression have better response to IFN-α therapy. Taken together, our findings elucidate that IFN-α could downregulate DPYD expression to inhibit EMT and HCC metastasis, and suggest that DPYD might be a potential prognostic biomarker and a therapeutic target for HCC.

Transcriptome-Wide Identification and Characterization of MYB Transcription Factor Genes in the Laticifer Cells of Hevea brasiliensis.

MYB transcription factors hold vital roles in the regulation of plant secondary metabolic pathways. Laticifers in rubber trees (Hevea brasiliensis) are of primary importance in natural rubber production because natural rubber is formed and stored within these structures. To understand the role of MYB transcription factors in the specialized cells, we identified 44 MYB genes (named HblMYB1 to HblMYB44) by using our previously obtained transcriptome database of rubber tree laticifer cells and the public rubber tree genome database. Expression profiles showed that five MYB genes were highly expressed in the laticifers. HblMYB19 and HblMYB44 were selected for further study. HblMYB19 and HblMYB44 bound the promoters of HbFDPS1, HbSRPP, and HRT1 in yeast. Furthermore, the transient overexpression of HblMYB19 and HblMYB44 in tobacco plants significantly increased the activity of the promoters of HbFDPS1, HbSRPP, and HRT1. Basing on this information, we proposed that HblMYB19 and HblMYB44 are the regulators of HbFDPS1, HbSRPP, and HRT1, which are involved in the biosynthesis pathway of natural rubber.

Independent relationship between body mass index and LH peak value of GnRH stimulation test in ICPP girls: A cross-sectional study.

The effect of obesity on idiopathic central precocious puberty (ICPP) girls is still under discussion. The relationship between body mass index (BMI) and sexual hormone levels of gonadotropin-releasing hormone (GnRH) stimulation test in ICPP girls is controversial and the underlying mechanism is unclear. This study aims to further explore the independent effect of excess adiposity on peak luteinizing hormone (LH) level of stimulation test in ICPP girls and the role of other related factors. A retrospective cross-sectional study was performed on 618 girls diagnosed as having ICPP, including 355 cases of normal weight, 99 cases of overweight and 164 cases of obese. The results showed that obese group had more progressed Tanner stage and no significant difference (P=0.28) in LH peak was found as basal LH value was used as a covariate. The obese group had higher total testosterone (TT), adrenocorticotrophic hormone (ACTH), 17-α hydroxyprogesterone (17-αOHP) and androstendione (AN), with significantly increased fasting insulin (FIN) and homeostasis model of assessment for insulin resistance index (HOMA-IR). Stratified analysis showed inconsistency of the relationship between BMI-standard deviation score (BMI-SDS) and LH peak in different Tanner stages (P for interaction=0.017). Further smoothing plot showed linear and non-linear relationship between BMI-SDS and LH peak in three Tanner stages. Then linear regression model was used to analyze the relationship between BMI-SDS and LH peak in different Tanner stages, with and without different confounding factors being adjusted. In B2 stage, BMI-SDS was negatively associated with LH peak. In B3 stage, when BMI-SDS <1.5, as BMI-SDS increased, the level of LH peak decreased (model I: ß=-1.8, 95% CI=-4.7 to 1.1, P=0.214). When BMI-SDS ≥1.5, BMI-SDS was significantly positively associated with LH peak (model I: ß=4.5, 95% CI=1.7 to 7.4, P=0.002). In B4 stage, when BMI-SDS <1.5, BMI-SDS was negatively associated with LH peak (model I: ß=-11.6, 95% CI=-22.7 to-0.5, P=0.049). When BMI-SDS ≥1.5, BMI-SDS was positively associated with LH peak (model I: ß=-4.2, 95% CI=-3.3 to 11.7, P=0.28). It is concluded that there is an independent correlation between BMI-SDS and LH peak of stimulation test in ICPP girls, their relationships are different in different Tanner stages, and the effect of BMI-SDS can be affected by adrenal androgens, estradiol and glucose metabolism parameters.

Hair growth promoting effect of white wax and policosanol from white wax on the mouse model of testosterone-induced hair loss.

White wax (WW) has been traditionally used to treat hair loss in China. However there has been no reporter WW and its extract responsible for hair growth-promoting effect on androgenetic alopecia. In this paper, we examined the hair growth-promoting effects of WW and policosanol of white wax (WWP) on model animal of androgenetic alopecia and the potential target cell of WW and WWP. WW (1, 10 and 20%) and WWP (0.5, 1 and 2%) were applied topically to the backs of mice. Finasteride (2%) was applied topically as a positive control. MTS assays were performed to evaluate cell proliferation in culture human follicle dermal papilla cells (HFDPCs). The inhibition of WW and WWP for 5α- reductase were tested in Vitro. Results showed more lost hairs were clearly seen in mice treated with TP only and TP plus vehicle. Mice which received TP plus WW and WWP showed less hair loss. WW and WWP showed an outstanding hair growth-promoting activity as reflected by the follicular length, follicular density, A/T ratio, and hair bulb diameter. The optimal treatment effect was observed at 10% WW and 1% WWP, which were better than 2% finasteride treatment. MTS assay results suggested that WW and WWP remarkably increased the proliferation of HFDPCs. Inhibitor assay of 5α- reductase showed that WW and WWP inhibited significantly the conversion of testosterone to dihydrotesterone, and the IC50 values of WW and WWP were higher than that of finasteride. In Conclusion, WW and WWP could act against testosterone-induced alopecia in mice, and they promoted hair growth by inhibiting 5α-reductase activity and HFDPCs proliferation. DPCs is the target cell of WW and WWP.