Elevated 2-oxoglutarate antagonizes DNA damage responses in cholangiocarcinoma chemotherapy through regulating aspartate beta-hydroxylase.

Cholangiocarcinoma (CCA) is resistant to systemic chemotherapies that kill malignant cells mainly through DNA damage responses (DDRs). Recent studies suggest that the involvement of 2-oxoglutarate (2-OG) dependent dioxygenases in DDRs may be associated with chemoresistance in malignancy, but how 2-OG impacts DDRs in CCA chemotherapy remains elusive. We examined serum 2-OG levels in CCA patients before receiving chemotherapy. CCA patients are classified as progressive disease (PD), partial response (PR), and stable disease (SD) after receiving chemotherapy. CCA patients classified as PD showed significantly higher serum 2-OG levels than those defined as SD and PR. Treating CCA cells with 2-OG reduced DDRs. Overexpression of full-length aspartate beta-hydroxylase (ASPH) could mimic the effects of 2-OG on DDRs, suggesting the important role of ASPH in chemoresistance. Indeed, the knockdown of ASPH improved chemotherapy in CCA cells. Targeting ASPH with a specific small molecule inhibitor also enhanced the effects of chemotherapy. Mechanistically, ASPH modulates DDRs by affecting ATM and ATR, two of the major regulators finely controlling DDRs. More importantly, targeting ASPH improved the therapeutic potential of chemotherapy in two preclinical CCA models. Our data suggested the impacts of elevated 2-OG and ASPH on chemoresistance through antagonizing DDRs. Targeting ASPH may enhance DDRs, improving chemotherapy in CCA patients.

The multiple reference range of mean uterine artery pulsatility index for natural and in vitro fertilization singletons during 11-14 gestational weeks.

Background: Ultrasonography of the uterine artery (UtA) in the first and second trimesters of pregnancy can assess uterine-placental blood perfusion and guide early clinical prevention. Establishing normal ranges of the UtA pulsatility index (UtA-PI) at 11-14 weeks of pregnancy is helpful for the early identification of high-risk pregnant women and improving the prognosis. This study aimed to establish a reference range of UtA-PI based on crown-rump length (CRL) for spontaneous and in vitro fertilization (IVF) singleton pregnancy during 11-14 weeks, respectively. Methods: A prospective study was performed at Peking Union Medical College Hospital. Healthy, low-risk women with a singleton pregnancy at 11-14 gestational weeks were consecutively recruited for this study from December 2017 to December 2020. All participants underwent routine prenatal ultrasound examination. The CRL of the fetus and the UtA-PI were measured in both uterine arteries, and average values were calculated. The LMS method was used to fit the percentile (P)5, P10, P25, P50, P75, P90, and P95 curves of the UtA-PI value of spontaneous and IVF singleton pregnancy with CRL changes, respectively. Results: A total of 1,962 pregnant women with normal fetuses were included in this study, including 1,792 pregnancies conceived naturally and 170 IVF fetuses. The UtA-PI reference range in the spontaneous pregnancy group was consistently higher than that in the IVF group during 11-14 weeks, and showed a statistically significant difference in UtA-PI for spontaneous and IVF pregnancies (P<0.001). According to the LMS method, each percentile curve of UtA-PI decreased with the increase of CRL in both the natural pregnancy group and the IVF group. The P95 range of UtA-PI for pregnant women with naturally conceived and IVF pregnancy was 2.74 to 2.11 and 2.50 to 1.94, respectively. The overall change of UtA-PI differentials of the two groups showed a downward trend and decreased slightly with the increase of CRL. Conclusions: This study provided a single-center, large sample of data and constructed a CRL-based reference value of UtA-PI for spontaneous and IVF singleton pregnancy, which provides a reliable basis for early UtA evaluation and early clinical decision-making during 11-14 gestational weeks.

[Characteristics and Management of High-risk Maternal Patients in General Tertiary Hospital].

Objective To analyze the characteristics of high-risk maternal patients and evaluate the multidisciplinary medical care system we established correspondingly. Method We collected and analyzed the medical records of high-risk maternal patients who received medical care from January 1,2017 to December 31,2020 in Peking Union Medical College Hospital. Results Ninety-eight high-risk maternal patients were included in this study,and 84.7%(83/98)of them were combined with different severe systemic diseases.Under the multidisciplinary medical care system,91 patients showed improved conditions and were discharged,and the other 7 cases had poor prognosis. Conclusions General tertiary hospitals in Beijing are receiving maternal patients with more high-risk complications.Considering the high risk and diverse diseases of maternal patients admitted to our hospital,we established a medical care system composed of a multidisciplinary panel of experts for high-risk maternal patients to improve the medical care and prognosis of the patients with high efficiency.

Maternal Serum Angiogenic Factor sFlt-1 to PlGF Ratio in Preeclampsia: A Useful Marker for Differential Diagnosis and Prognosis Evaluation in Chinese Women.

The ratio of soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) is elevated and proved to be useful in preeclampsia (PE) diagnosis. Its value in differential diagnosis with other pregnancy complications and prediction of pregnancy duration has yet to be clarified in Chinese population. We retrospectively analyzed 118 singleton pregnancies with suspected or diagnosed PE at the Peking Union Medical College Hospital (PUMCH) in China. Among these, 62 pregnancies were diagnosed as PE (48 early onsets and 14 late onsets, with 39 and 5 severe PE, respectively), 12 gestational hypertension (GH), 15 chronic hypertension (chrHTN), 16 autoimmune diseases, and 13 pregnancies with uncomplicated proteinuria. And 76 normal pregnancies were included as control. The results showed (1) the sFlt-1/PlGF ratio in early onset PE subgroup was significantly higher than that in GH, chrHTN, and control groups; the sFlt-1/PlGF ratio in late onset PE subgroup was significantly higher than that in chrHTN and control groups, but similar as GH group; the sFlt-1/PlGF ratio was similar among GH, chrHTN, and control groups. (2) The sFlt-1/PlGF ratio was significantly increased in the PE group compared with autoimmune disease and uncomplicated proteinuria pregnancies. (3) By ROC curve analysis, the cutoff value of the sFlt-1/PlGF ratio was less than 21.5 to rule out PE and higher than 97.2 to confirm the diagnosis of PE. (4) The sFlt-1/PlGF ratio was higher in PE pregnancies delivering within 7 days than those more than 7 days, either in early onset PE or severe PE. In conclusion, we show that maternal sFlt-1/PlGF ratio is an efficient biomarker in the diagnosis and differential diagnosis of PE. This ratio can be used to predict the timing of delivery for PE pregnancies.

Aspartate beta-hydroxylase promotes cholangiocarcinoma progression by modulating RB1 phosphorylation.

Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth. Knockdown of ASPH expression inhibited CCA development and growth by reducing RB1 phosphorylation. Expression of ASPH promoted direct protein interaction between RB1, cyclin-dependent kinases, and cyclins. Treatment with 2-OG-dependent dioxygenase and ASPH inhibitors suppressed the interaction between RB1 and CDK4 as well as RB1 phosphorylation. Knockdown of ASPH expression inhibited CCA progression and RB1 phosphorylation in vivo and they were found to be highly expressed in human CCAs. Knockdown of ASPH expression altered CCA development by modulating RB1 phosphorylation, as one of the major factors regulating the growth of these tumors.

Preterm Births in Peking Union Medical College Hospital in the Past 25 Years.

Objective To investigate the changes in preterm birth rate,its gestational age distribution,and possible contributors in Peking Union Medical College Hospital (PUMCH) over the last 25-year period. Methods The clinical data of premature deliveries,both singleton and twins,in PUMCH from January 1,1990 to December 31,2014 were retrospectively analyzed. We counted the number of premature fetuses and assessed the changes of preterm birth rate and its gestational age distribution (including extremely preterm birth,early preterm birth,and late preterm birth) over time. The etiologies (including spontaneous and iatrogenic) of preterm birth were also surveyed. Results The overall preterm birth rate was 7.8% in PUMCH,showing a slightly up-trend in both singletons and twins. Twin prematurity accounted for 23.8% of total preterm births,increased from 15.1% to 28.5%. Preterm births subgrouped by gestational age included 26 cases (0.7%) of extreme prematurity (<28 weeks),1199 cases (33.9%) of early preterm birth (28- 33+6 weeks),and 2310 cases (65.3%) of late preterm birth (34- 36+6 weeks). The gestational age distribution in singletons and twins showed no significant difference(z=0.844,P=0.398). Changes in the proportion of preterm birth before 28 weeks was little,gradually increased in the 28- 33+6 weeks group (from 23.8% to 36.1%) and gradually decreased in the 34- 36+6 weeks group (from 75.5% to 63.3%). Trends of gestational age distribution of singleton and twins were similar to that of the total. Spontaneous preterm labor,preterm premature rupture of membrane,and medically indicated (iatrogenic) preterm birth accounted for 20.2%,38.9%,and 40.9% respectively. There was no difference in singletons and twins(χ2=1.071,P=0.301).The proportion of iatrogenic preterm was increased. Common reasons for iatrogenic preterm birth included gestational hypertension,fetal indications (including fetal distress,fetal growth restriction),placenta previa,and pregnancy complicated by heart disease. Conclusions The overall preterm birth rate shows an upward trend in the general hospital as a result of more multifetal gestations and more medically indicated preterm births. Reducing multifetal gestations and effective control of pregnancy complications should be the priorieties in preterm birth intervention.

[Correlation between neonatal vitamin D level and maternal vitamin D level].

OBJECTIVE: To investigate the correlation between neonatal and maternal vitamin D levels. METHODS: From June 1 to July 10, 2015, umbilical venous blood samples were collected from 102 full-term single neonates, and venous blood samples were collected from their mothers. Ultra-performance liquid chromatography with isotope dilution was applied to measure the serum 25(OH)D level. RESULTS: Vitamin D insufficiency was found in 39 mothers (38.2%) and 27 neonates (26.5%), and vitamin D deficiency was found in 25 mothers (24.5%) and 66 neonates (64.7%). Neonatal serum 25(OH)D level differed significantly between the groups of mothers with different serum 25(OH)D levels (P<0.001). Maternal 25(OH)D level was positively correlated with neonatal vitamin D level (r=0.914, P<0.001). When the receiver operating characteristic curve for maternal 25(OH)D level was used to predict neonatal vitamin D deficiency (≤15 ng/mL), the area under the curve was 0.962 (95%CI: 0.930-0.994; P<0.001). The sensitivity and specificity of maternal serum 25(OH)D level≤27.55 ng/mL to predict neonatal vitamin D deficiency were 97.2% and 80.3%, respectively. CONCLUSIONS: Neonatal vitamin D level is positively correlated with maternal vitamin D level. Maternal vitamin D level can help to predict neonatal vitamin D deficiency.

Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-ß-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma.

Abundant expression of aspartyl-(asparaginyl)-ß-hydroxylase (AAH) correlates with infiltrative growth of hepatocellular carcinoma (HCC). Herein, we examine the role of phosphorylation in relation to AAH's protein expression, hydroxylase activity, promotion of cell motility, and activation of Notch signaling in human Huh7 hepatoma cells. Predicted glycogen synthase kinase-3ß (GSK-3ß), protein kinase A (PKA), protein kinase C (PKC), and casein kinase 2 (CK2) phosphorylation sites encoded by human AAH cDNA were ablated by S/T→A site-directed mutagenesis using N-Myc-tagged constructs in which gene expression was controlled by a cytomegalovirus promoter. Functional consequences were assessed in transiently transfected Huh7 cells. Cells transfected with wildtype AAH had significantly increased AAH expression, catalytic activity, HES-1 expression, and directional motility relative to controls. Single phosphorylation site mutations in the C-terminus largely abrogated these effects and further inhibited catalytic activity relative to that in cells transfected with empty vector, whereas the effects of single point mutations within the N-terminus were more varied. In contrast, AAH cDNAs carrying multiple phosphorylation site mutations exhibited wildtype levels of AAH catalytic activity suggesting that the effects of AAH phosphorylation are complex and non-uniform. AAH expression and function can be modulated by direct phosphorylation of the protein. These findings suggest additional strategies for inhibiting infiltrative growth of HCC.

Regulation of Aspartyl-(Asparaginyl)-ß-Hydroxylase Protein Expression and Function by Phosphorylation in Hepatocellular Carcinoma Cells.

BACKGROUND: Asparaginyl-ß-hydroxylase (AAH) promotes cell adhesion, migration, and invasion via Notch activation. AAH's expression is up-regulated by insulin/IGF signaling through PI3K-Akt, but its protein is independently regulated by GSK-3ß. The multiple predicted GSK-3ß phosphorylation sites suggest post-translational mechanisms may regulate AAH protein expression. METHODS: Human Huh7 hepatoma cells were transfected with recombinant plasmids that expressed full-length N-terminal Myc-tagged (N-Myc-AAH) or C-terminal HA-tagged (C-HA-AAH) cDNA. Effects of IGF-1 on AAH protein were examined using cellular ELISAs, immunofluorescence, and Western blotting. Effects of kinase inhibitors relevant to AAH's predicted phosphorylation sites were studied. RESULTS: IGF-1 stimulation increased AAH protein expression and shifted AAH's localization from the perinuclear zone to the cell periphery, including podocytes. Subsequently, Notch-1 intracellular domain was translocated to the nucleus, which is critical for Notch- modulated gene expression. Besides GSK-3ß, inhibition of PKC, PKA, and CK2, which could potentially phosphorylate AAH, increased IGF-1 stimulated AAH protein. Finally, insulin and LiCl independently and additively increased long-term AAH protein expression. CONCLUSION: Insulin/IGF-1 stimulation of AAH and Notch are enhanced by inhibiting kinases that could phosphorylate AAH protein. Targeted manipulation of AAH's phosphorylation state may have therapeutic value for reducing AAH-Notch activation and attendant infiltrative growth of hepatocellular carcinomas.

[Multilayer mirrors used for the moon-based EUV imager].

The EUV imager is used to observe the 30.4 nm radiation of the earth's plasmasphere on the lunar surface. The 30.4 nm multilayer is the key optical part of the imager. According to the technical parameters, the B4 C/Mg, B4 C/Mg2Si, B4 C/Al, B4 C/Si, Mo/Si and so on were chosen. The period thickness, ratio of the material and the number of the periods were optimized and the reflectivity of those multilayers were calculated. In consideration of the lunar environment, the Mo/Si and the B4 C/Si multilayer were deposited by magnetron sputtering coating plant. The reflectivity of Mo/Si and B4 C/Si multilayer at 30.4 nm is 15.3% and 22.8% respectively.

Phosphorylation Modulates Aspartyl-(Asparaginyl)-ß Hydroxylase Protein Expression, Catalytic Activity and Migration in Human Immature Neuronal Cerebellar Cells.

BACKGROUND: Abundant aspartyl-asparaginyl-ß-hydroxylase (ASPH) expression supports robust neuronal migration during development, and reduced ASPH expression and function, as occur in fetal alcohol spectrum disorder, impair cerebellar neuron migration. ASPH mediates its effects on cell migration via hydroxylation-dependent activation of Notch signaling networks. Insulin and Insulin-like growth factor (IGF-1) stimulate ASPH mRNA transcription and enhance ASPH protein expression by inhibiting Glycogen Synthase Kinase-3ß (GSK-3ß). This study examines the role of direct GSK-3ß phosphorylation as a modulator of ASPH protein expression and function in human cerebellar-derived PNET2 cells. METHODS: Predicted phosphorylation sites encoded by human ASPH were ablated by S/T→A site-directed mutagenesis of an N-Myc-tagged wildtype (WT) cDNA regulated by a CMV promoter. Phenotypic and functional features were assessed in transiently transfected PNET2 cells. RESULTS: Cells transfected with WT ASPH had increased ASPH protein expression, directional motility, Notch-1 and Jagged-1 expression, and catalytic activity relative to control. Although most single- and multi-point ASPH mutants also had increased ASPH protein expression, their effects on Notch and Jagged expression, directional motility and adhesion, and catalytic activity varied such that only a few of the cDNA constructs conferred functional advantages over WT. Immunofluorescence studies showed that ASPH phosphorylation site deletions can alter the subcellular distribution of ASPH and therefore its potential interactions with Notch/Jagged at the cell surface. CONCLUSIONS: Inhibition of ASPH phosphorylation enhances ASPH protein expression, but attendant alterations in intra-cellular trafficking may govern the functional consequences in relation to neuronal migration, adhesion and Notch activated signaling.

[Clinical analysis of pregnancies after vaginal radical trachelectomy].

OBJECTIVE: To explore the pregnancy outcome and obstetric management of pregnancy and delivery after vaginal radical trachelectomy (VRT). METHODS: Forty-two cases of VRT from December 2003 to May 2012 in Peking Union Medical College Hospital were analyzed retrospectively. Among them ten cases got pregnant successfully. RESULTS: The average age of patient at VRT surgery was (30.6 ± 3.7) years old and average follow-up time was 29.5 months. There were 31 patients attempted conception. Ten of them got fourteen conceptions successfully. Overall conception rate was 45% (14/31). There were four cases of first trimester abortion. Among them, two were miscarriage, two were elective abortion. There was one case of ectopic pregnancy operation and non of second trimester loss. Nine cases reached the third trimester. The total preterm delivery rate was 4/9. There were two cases delivered before 32 gestational weeks (2/9). Cesarean section was performed through a transverse incision in all of nine cases. No uterine rupture and postpartum hemorrhage occurred. All newborns had good outcomes. The average follow-up time after postpartum was 22.9 months. All cases were disease-free. CONCLUSIONS: The conception rate of patients after VRT in our series is 45%. The preterm birth rate of pregnancy after VRT is higher. Routine cerclage of cervix during VRT procedure and pregnancy is not necessary. Cesarean section shortly after full term pregnancy through a transverse incision should be considered as a suitable and safe procedure.

[Proteomic analysis of novel serum markers in first-episode schizophrenics before versus after treatment of risperidone].

OBJECTIVE: To explore the changes in serum protein levels of schizophrenics before and after treatment of risperidone and identify the potential markers of diagnosis, treatment and drug side effects of schizophrenia. METHODS: Eighty first-episode schizophrenics without other concurrent diseases and with positive and negative symptom scale (PANSS) score greater than or equal to 60 were recruited. And 15 of them were measured by proteomics. Different serum levels of proteins were obtained from these patients and were separated by two-dimensional electrophoresis (2-DE) before and after a single risperidone treatment for 8 weeks. These proteins were then identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and peptide mass fingerprinting. Enzyme-linked immunosorbent assay (ELISA) was used to verify the results. RESULTS: Almost 1400 spots were detected by 2-DE in each gel. Of these proteins, 23 protein spots showed significant differences in abundance before and after risperidone treatment. After MALDI-TOF peptide mass fingerprinting, 9 up-regulated proteins and 8 down-regulated proteins were validated after treatment. Of these proteins, the schizophrenics showed a significantly higher content of apolipoprotein A-1 (APOA-1) than those before treatment and haptoglobin (HP) protein was down-regulated after treatment. The results of ELISA were parallel with those of proteomic (P < 0.01). CONCLUSION: The serum proteins correlated with blood glucose and lipid metabolism are altered in schizophrenia after treatment of risperidone. A clinician should monitor the side effects of antipsychotic drugs according to the changes of serum proteins.

Phospho-SXXE/D motif mediated TNF receptor 1-TRADD death domain complex formation for T cell activation and migration.

In TNF-treated cells, TNFR1, TNFR-associated death domain protein (TRADD), Fas-associated death domain protein, and receptor-interacting protein kinase proteins form the signaling complex via modular interaction within their C-terminal death domains. In this paper, we report that the death domain SXXE/D motifs (i.e., S381DHE motif of TNFR1-death domain as well as S215LKD and S296LAE motifs of TRADD-death domain) are phosphorylated, and this is required for stable TNFR1-TRADD complex formation and subsequent activation of NF-κB. Phospho-S215LKD and phospho-S296LAE motifs are also critical to TRADD for recruiting Fas-associated death domain protein and receptor-interacting protein kinase. IκB kinase ß plays a critical role in TNFR1 phosphorylation of S381, which leads to subsequent T cell migration and accumulation. Consistently, we observed in inflammatory bowel disease specimens that TNFR1 was constitutively phosphorylated on S381 in those inflammatory T cells, which had accumulated in high numbers in the inflamed mucosa. Therefore, SXXE/D motifs found in the cytoplasmic domains of many TNFR family members and their adaptor proteins may serve to function as a specific interaction module for the α-helical death domain signal transduction.

The Evi1, microRNA-143, K-Ras axis in colon cancer.

MicroRNA profiling of diseased/non-diseased tissue has identified expression signatures associated with a wide range of pathogenic conditions including malignancy. For example, colon cancer is associated with the under expression of miRNA-143 yet the molecular etiology of under expression is unknown. The K-Ras oncogene is a target of miRNA-143. Here, we show that the ecotropic viral integration site 1 oncoprotein (Evi1) is a transcriptional suppressor of the miRNA-143 gene. We find an indirect relationship between miRNA-143 and Evi1 expression. A complex molecular axis linking Evi1, miRNA-143 is operational in human colon cancer.

Acetylation modulates prolactin receptor dimerization.

Cytokine-activated receptors undergo extracellular domain dimerization, which is necessary to activate intracellular signaling pathways. Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent. PRLR-recruited CREB-binding protein (CBP) acetylates multiple lysine sites randomly distributed along the cytoplasmic loop of PRLR. Two PRLR monomers appear to interact with each other at multiple parts from the membrane-proximal region to the membrane-distal region, relying on the coordination among multiple lysine sites neutralized via acetylation. Cytoplasmic loop-dimerized PRLR activates STAT5, which is also acetylated by CBP and undergoes acetylation-dependent dimerization. PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat-like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation.

Effectiveness of microRNA in Down-regulation of TGF-beta gene expression in digital flexor tendons of chickens: in vitro and in vivo study.

PURPOSE: Transforming growth factor (TGF)-beta is considered to be responsible for the formation of scars such as adhesions around healing digital flexor tendons. We proposed to deliver microRNAs (miRNAs) to silence expression of the TGF-beta1 gene and to investigate the effectiveness of miRNAs in down-regulation of the TGF-beta1 gene in vitro and in vivo. METHODS: We designed and engineered 4 miRNAs according to genetic sequences of chicken TGF-beta1. Four plasmid vectors harboring the respective engineered miRNAs and 1 control vector were constructed. We transfected 30 wells of cultured tenocytes with these vectors and harvested them 48 hours later. The gene expression levels were quantified using real-time polymerase chain reactions. Subsequently, the miRNA that most effectively silenced TGF-beta gene in vitro was tested on 25 chickens in vivo. The miRNA and control vectors were injected into the injured tendons, respectively. At 1 and 6 weeks after surgery, the tendons were analyzed for gene expression and protein production. RESULTS: In both in vitro and in vivo settings, delivery of miRNA to the tendon substantially down-regulated expression of the TGF-beta gene but did not affect expression of the collagen I gene. In the healing tendon, TGF-beta gene expression was significantly down-regulated by 50% to 60% at 1 and 6 weeks. At 6 weeks, the collagen III gene expression was significantly down-regulated by 55% at 6 weeks and the connective tissue growth factor gene was significantly down-regulated by 25%. At 6 weeks, TGF-beta protein was substantially decreased. CONCLUSIONS: MicroRNA significantly down-regulates expression of the TGF-beta in vitro and in vivo. Application of miRNA did not down-regulate expression of the collagen I, but downregulated the collagen III gene. Application of miRNA treatment to modulate TGF-beta expression holds great promise in preventing tendon adhesion formation.

MicroRNA 125a and its regulation of the p53 tumor suppressor gene.

MicroRNA (miRNA) are a class of non-coding RNA that suppress gene expression by degradation or translational inhibition of target RNA. Several miRNA have been shown to target oncogenes and recently miRNA-125b was shown to translationally and transcriptionally inhibit the p53 gene. Here, we show that an additional isomer of miRNA-125 (miRNA-125a) translationally arrests mRNA of the p53 tumor suppressor gene. The basis of this activity is the high degree of sequence homology between the seed sequence of miR-125a and the 3'-UTR of p53. Our findings add miRNA-125a to the growing list of miRNA with oncogenic targets.

Continuous albendazole therapy in alveolar echinococcosis: long-term follow-up observation of 20 cases.

Twenty patients with primary hepatic alveolar echinococcosis were treated with continuous long-term albendazole at a dose of 20 mg/kg/d for an average of 5.7 years (1.5-13.5 years) and were followed up for an average of 12.7 years (4.1-13.5 years). The therapeutic effects were evaluated by clinical, laboratory (haemogram, liver function tests), ultrasonography and computed tomography (CT) examinations. The CT pattern of hepatic lesions was classified into three types: solid form (5 cases), pseudocystic form (6 cases) and 'geographic map' (mixed) form (9 cases). Short-term results were encouraging. Jaundice and haemoptysis disappeared within 1 month of starting treatment, and hemiparesis in a patient with cerebral metastases also gradually improved. Treatment was less effective in two patients with advanced disease. On long-term follow-up, three patients were apparently cured, and the remaining 17 patients showed a good initial response, but recurrence occurred in 13 patients (65%). Therapeutic outcome was favourable with the solid form, but poor with the pseudocystic form. The mixed form was a transitional phase and slowly progressive. Involvement of the porta hepatis was the cause of various complications with high morbidity and mortality. Five patients (25%) died during the period of observation, the 10-year survival rate being, therefore, 75%.

Influential and prognostic factors of small for gestational age infants.

BACKGROUND: Small for gestational age (SGA) infants are associated with a high rate of oligohydramnios, stillbirth and cesarean delivery. Among SGA patients there is a higher risk of neonatal complications, such as polycythemia, hyperbilirubinemia, and hypothermia. Additionally, the SGA infant is prone to suffer from major neurologic sequelae, as well as cardiovascular system disease, in later life. Proper monitoring and therapy during pregnancy are, therefore, of utmost importance. The present study aimed to investigate the influential and prognostic factors of SGA infants. METHODS: From January 2001 to June 2007, a total of 55 SGA neonatal infants were included in a study group. All were born at Peking Union Medical College Hospital, with regular formal antenatal examinations. In addition, a total of 122 cases of appropriate for gestational age (AGA) infants were born at the same time and were registered into a control group. All cases were singleton pregnancies with detailed information of the maternal age, gravidity, parity, maternal height and weight, complications, uterine height and abdominal circumference, results from transabdominal ultrasonography between 32 - 38 gestational weeks, pregnancy duration, delivery manner, placenta, umbilical cord, and neonatal complications. RESULTS: Significant differences were observed in placenta weight and neonatal malformations between the study and control groups. Multivariate analysis revealed increased parity, maternal hyperthyroidism and hyperthyroidism history as risk factors. Fetal abdominal circumferences less than 30 and 32 cm at 32 - 38 gestational weeks respectively, as determined by ultrasonography, resulted in a Youden index of 0.62. CONCLUSIONS: SGA infants were associated with a greater risk of smaller placentas and infant malformations. Increased parity, maternal hyperthyroidism, and a hyperthyroid history were risk factors for SGA infants. Fetal abdominal circumference less than 30 cm at 32 gestational weeks and less than 32 cm at 38 weeks, as determined by ultrasonography, was considered an effective index for SGA.