Organ-delimited gene regulatory networks provide high accuracy in candidate transcription factor selection across diverse processes.

Organ-specific gene expression datasets that include hundreds to thousands of experiments allow the reconstruction of organ-level gene regulatory networks (GRNs). However, creating such datasets is greatly hampered by the requirements of extensive and tedious manual curation. Here, we trained a supervised classification model that can accurately classify the organ-of-origin for a plant transcriptome. This K-Nearest Neighbor-based multiclass classifier was used to create organ-specific gene expression datasets for the leaf, root, shoot, flower, and seed in Arabidopsis thaliana. A GRN inference approach was used to determine the: i. influential transcription factors (TFs) in each organ and, ii. most influential TFs for specific biological processes in that organ. These genome-wide, organ-delimited GRNs (OD-GRNs), recalled many known regulators of organ development and processes operating in those organs. Importantly, many previously unknown TF regulators were uncovered as potential regulators of these processes. As a proof-of-concept, we focused on experimentally validating the predicted TF regulators of lipid biosynthesis in seeds, an important food and biofuel trait. Of the top 20 predicted TFs, eight are known regulators of seed oil content, e.g., WRI1, LEC1, FUS3. Importantly, we validated our prediction of MybS2, TGA4, SPL12, AGL18, and DiV2 as regulators of seed lipid biosynthesis. We elucidated the molecular mechanism of MybS2 and show that it induces purple acid phosphatase family genes and lipid synthesis genes to enhance seed lipid content. This general approach has the potential to be extended to any species with sufficiently large gene expression datasets to find unique regulators of any trait-of-interest.

Assisted reproductive technology and neurodevelopmental outcomes in offspring: a prospective birth cohort study in East China.

RESEARCH QUESTION: Is ART associated with adverse neurodevelopmental outcome in 12-month-old offspring compared with those conceived through natural conception? DESIGN: In this prospective cohort study, 488 infertile women undergoing ART and 1397 women with natural conception were recruited and followed until their offspring were 12 months old. The primary outcome was the neurodevelopment in the offspring. The association between exposure to ART and Gesell developmental scale scores was investigated using multiple linear regression models after adjusting for confounders. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to verify the results. RESULTS: In total, 18 (3.7%) and 40 (2.9%) children in the ART and natural conception groups, respectively, had been diagnosed with neurodevelopmental delay at 12 months of age. It was found that gross motor, adaptive behaviour, language and total development quotient scores were comparable between the groups. Following multivariate linear regression and IPTW, social behaviour development quotient scores were found to be slightly higher in the ART group than the natural conception group. Higher social behaviour development quotient scores in the ART group were also observed in the male and the singleton subgroups. CONCLUSIONS: At 12 months, offspring born after ART appeared to have similar motor, language and adaptive behaviour skills, and total development quotient scores, to those born after natural conception. However, social behaviour development in 12-month-old infants was slightly higher in those conceived using ART than in naturally conceived offspring, especially in male or singleton infants. These findings may provide new information in evaluating the potential benefits and risks of ART.

Application of Dynamic 18F-FDG PET/CT for Distinguishing Intrapulmonary Metastases from Synchronous Multiple Primary Lung Cancer.

It has been a big challenge to distinguish synchronous multiple primary lung cancer (sMPLC) from primary lung cancer with intrapulmonary metastases (IPM). We aimed to assess the clinical application of dynamic 18F-FDG PET/CT in patients with multiple lung cancer nodules. We enrolled patients with multiple pulmonary nodules who had undergone dynamic 18F-FDG PET/CT and divided them into sMPLC and IPM groups based on comprehensive features. The SUVmax, fitted K i value based on dynamic scanning, and corresponding maximum diameter (D max) from the two largest tumors were determined in each patient. We determined the absolute between-tumor difference of SUVmax/D max and K i /D max (ΔSUVmax/D max; ΔK i /D max) and assessed the between-group differences. Further, the diagnostic accuracy was evaluated by ROC analysis and the correlation between ΔSUVmax/D max and ΔK i /Dmax from all groups was determined. There was no significant difference for ΔSUVmax/D max between the IPM and sMPLC groups, while the IPM group had a significantly higher ΔK i /Dmax than the sMPLC group. The AUC of ΔK i /D max for differentiating sMPLC from IPM was 0.80 (cut-off value of K i = 0.0059, sensitivity 79%, specificity 75%, p < 0.001). There was a good correlation (Pearson r = 0.91, 95% CI: 0.79-0.96, p < 0.0001) between ΔSUVmax/D max and ΔK i /D max in the IPM group but not in the sMPLC group (Pearson r = 0.45, p > 0.05). Dynamic 18F-FDG PET/CT could be a useful tool for distinguishing sMPLC from IPM. K i calculation based on Patlak graphic analysis could be more sensitive than SUVmax in discriminating IPM from sMPLC in patients with multiple lung cancer nodules.

Efficacy and safety of bicyclol for treating patients with idiosyncratic acute drug-induced liver injury: A multicenter, randomized, phase II trial.

BACKGROUND AND AIMS: Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI. METHODS: This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority and phase II trial. Patients with idiosyncratic acute DILI were randomized 1: 1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID) and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment for 4 weeks. RESULTS: Overall, 241 patients were included in the full analysis set, with 81, 82 and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups respectively. ALT levels decreased across groups (-249.2 ± 151.1, -273.6 ± 203.1, and -180.8 ± 218.2 U/L in the low-dose bicyclol, high-dose bicyclol and control groups, respectively; both p < .001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6 and 8 were higher in the bicyclol-dependent groups than in the control group (p = .002 at week 1 and all p < .001 at weeks 2, 4, 6 and 8 respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol and control groups were 29, 16 and 43 days respectively. Adverse events, serious adverse events and adverse drug reactions were similar across groups. CONCLUSIONS: Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy. TRIAL REGISTRATION NUMBER: www. CLINICALTRIALS: gov (registration no. NCT02944552).

Design and synthesis of boron-containing ALK inhibitor with favorable in vivo efficacy.

ALK is an attractive therapeutic target for the treatment of non-small cell lung cancer. As an emerging element in medicinal chemistry, boron has achieved great success in the discovery of antitumor drugs and antibacterial agents. Through construction of a BCC (boron-containing compound) compound library and broad kinase screening, we found the ALK inhibitor hit compound 10a. Structural optimization by CADD and isosterism revealed that lead compound 10k has improved activity (ALKL1196M IC50 = 8.4 nM, NCI-H2228 cells IC50 = 520 nM) and better in vitro metabolic stability (human liver microsomes, T1/2 = 238 min). Compound 10k showed good in vivo efficacy in a nude mouse NCI-H2228 lung cancer xenograft model with a TGI of 52 %. Molecular simulation analysis results show that the hydroxyl group on the oxaborole forms a key hydrogen bond with Asn1254 or Asp1270, and this binding site provides a new idea for drug design. This is the first publicly reported lead compound for a boron-containing ALK inhibitor.

Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder.

Imaging markers sensitive to neurodegeneration in the substantia nigra are critically needed for future disease-modifying trials. Previous studies have demonstrated the utility of posterior substantia nigra free water as a marker of progression in Parkinson's disease. In this study, we tested the hypothesis that free water is elevated in the posterior substantia nigra of idiopathic REM sleep behaviour disorder, which is considered a prodromal stage of synucleinopathy. We applied free-water imaging to 32 healthy control subjects, 34 patients with idiopathic REM sleep behaviour disorder and 38 patients with Parkinson's disease. Eighteen healthy control subjects and 22 patients with idiopathic REM sleep behaviour disorder were followed up and completed longitudinal free-water imaging. Free-water values in the substantia nigra were calculated for each individual and compared among groups. We tested the associations between posterior substantia nigra free water and uptake of striatal dopamine transporter in idiopathic REM sleep behaviour disorder. Free-water values in the posterior substantia nigra were significantly higher in the patients with idiopathic REM sleep behaviour disorder patients than in the healthy control subjects, but were significantly lower in patients with idiopathic REM sleep behaviour disorder than in patients with Parkinson's disease. In addition, we observed significantly negative associations between posterior substantia nigra free-water values and dopamine transporter striatal binding ratios in the idiopathic REM sleep behaviour disorder patients. Longitudinal free-water imaging analyses were conducted with a linear mixed-effects model, and showed a significant Group × Time interaction in posterior substantia nigra, identifying increased mean free-water values in posterior substantia nigra of idiopathic REM sleep behaviour disorder over time. These results demonstrate that free water in the posterior substantia nigra is a valid imaging marker of neurodegeneration in idiopathic REM sleep behaviour disorder, which has the potential to be used as an indicator in disease-modifying trials.

Near-infrared fluorescence imaging-guided lymphatic mapping in thoracic esophageal cancer surgery.

PURPOSE: Identifying the lymphatic drainage pathway is important for accurate lymph node (LN) dissection in esophageal cancer (EC). This study aimed to assess lymphatic drainage mapping in thoracic EC using near-infrared fluorescent (NIRF) imaging with indocyanine green (ICG) and identify its feasibility for intraoperative LN drainage visualization and dissection. METHODS: From November 2019 to August 2020, esophagectomy was performed using intraoperative NIRF navigation with ICG injected into the esophageal submucosa by endoscopy. All LNs were divided into four groups according to the NIRF status and presence of metastasis: NIRF+LN+, NIRF+LN-, NIRF-LN+, and NIRF-LN-. RESULTS: Regional LNs were detected in all 84 enrolled patients with thoracic EC. A total of 2164 LNs were removed, and the mean number of dissected LNs was 25.68 ± 12.00. NIRF+ LNs were observed in all patients and distributed at 19 LN stations, which formed lymphatic drainage maps. The top five LN stations of NIRF+ probability in upper thoracic EC were No. 7, 106ecR, 107, 1, and 106recL; in middle thoracic EC, they were No. 107, 7, 110, 1, and 105; and in lower thoracic EC, they were No. 107, 7, 110, 106recR, and 1. There were no cases of ICG-related adverse events or chylothorax. The 30-day mortality rate was 0%. Major complications included anastomotic fistula (7.14%), pneumonia (4.76%), pleural effusion (13.10%), atelectasis (3.75%), hoarseness (8.33%), and arrhythmia (4.76%). CONCLUSION: Regional LN mapping of thoracic EC was performed using ICG/NIRF imaging, which showed different preferred LN drainage stations in various anatomical locations of the thoracic esophagus. ICG/NIRF imaging is feasible for intraoperative LN drainage visualization and dissection. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT04173676 ( http://www. CLINICALTRIALS: gov/ ).

Association of homocysteine with IVF/ICSI outcomes stratified by MTHFR C677T polymorphisms: a prospective cohort study.

RESEARCH QUESTION: What is the association between homocysteine (Hcy) and IVF/intracytoplasmic sperm injection (ICSI) outcomes, stratified by methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms? DESIGN: This prospective cohort study recruited 1011 infertile women undergoing IVF/ICSI treatment for the first time at the International Peace Maternity and Child Health Hospital between June 2015 and March 2018. RESULTS: The concentration of total serum Hcy was significantly negatively associated with clinical pregnancy and implantation rate. When adjusted for maternal and paternal age and educational level, maternal body mass index, and FSH and oestradiol concentrations, logistic regression analysis showed that women with higher Hcy had a higher risk of unsuccessful pregnancy. After stratification by MTHFR C677T polymorphisms and adjustment for confounding factors, a higher risk of unsuccessful pregnancy and a significantly lower implantation rate only existed in women with higher Hcy concentration in the MTHFR C677T TT genotype. There was no significant association between Hcy concentrations and other ovarian stimulation outcomes (oocytes retrieved, metaphase II stage oocytes, fertilization rate, cleavage rate, high-quality embryo rate) or neonatal outcomes (preterm birth, gestational age at delivery, Caesarean section, birthweight, small for gestational age, large for gestational age or birth defects). CONCLUSIONS: Hcy is highly negatively associated with clinical pregnancy and implantation rate during the first IVF/ICSI cycle, especially in women carrying the MTHFR C677T TT genotype. Other factors with impacts on reproductive outcomes, such as stage of embryo transferred, other factors involved in folate metabolism, preimplantation genetic testing, etc., should be taken into account in further research.

Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton.

The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.

Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors.

Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) are very promising targets for hematological malignancies and autoimmune diseases. In recent years, a few compounds have been approved as a marketed medicine, and several are undergoing clinical trials. By recombining the dominant backbone of known active compounds, constructing a foused library, and screening a broad panel of kinases, we found a class of compounds with dual activities of anti-BTK and anti-JAK3. Some of the compounds have shown 10-folds more active in the enzyme and cell-based assays than a known active compound. Furthermore, liver microsome stability experiments show that these compounds have better stability than ibrutinib. These explorations offered new clues to discover benzoxaborole fragment and pyrimidine scaffold as more effective BTK and JAK3 dual inhibitors.

Predictive Value of Anastomotic Blood Supply for Anastomotic Stricture After Esophagectomy in Esophageal Cancer.

BACKGROUND: Insufficient blood supply in the gastric tube is considered as a risk factor for postoperative anastomotic strictures in patients receiving esophagectomy, but the direct evidence is lacking. AIMS: We aimed to investigate the correlation between perioperative blood supply in the anastomotic area of the gastric tube and the formation of anastomotic strictures in the patients undergoing esophagectomy. METHODS: This prospective study included 60 patients with esophageal squamous cell carcinoma undergoing Ivor Lewis esophagectomy between March 2014 and February 2016, which were divided into stricture group (n = 13) and non-stricture group (n = 47) based on their severity of anastomotic strictures at 3 months post-operation. The perioperative anastomotic blood supply was measured using a laser Doppler flowmetry. The gastric intramucosal pH (pHi) was measured by a gastric tonometer within 72 h post-operation. The perfusion index and gastric pHi were compared between groups. RESULTS: The stricture group had a significantly lower blood flow index (P < 0.001) and gastric pHi values from day 1 to day 3 post-operation than the non-stricture group (all P < 0.001). In addition, Pearson correlation analysis showed that both the perfusion index and gastric pHi were significantly correlated with stricture size and stricture scores, respectively (r = 0.65 - 0.32, all P < 0.05). Furthermore, the multivariate logistic regression analysis showed that perfusion index was an influential factor associated with postoperative anastomotic strictures (OR 0.84. 95% CI 0.72-0.98, P = 0.026). CONCLUSION: These results suggested that poor blood supply in the anastomotic area of the gastric tube in the perioperative period was a risk factor for postoperative anastomotic strictures.

MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations.

OBJECTIVE: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs. METHODS: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics. RESULTS: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development. INTERPRETATION: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371-384.

Photodiode array for characterizing optical fibers.

An innovative approach is proposed and demonstrated for measuring the attenuation of light in optical fibers. The technique utilizes a silicon device containing a v-groove that positions the fiber and detector array along the v-groove. The detectors within the v-groove are designed to partially surround the fiber in order to maximize the coupling of scattered light from the fiber into each detector.

Study of disease phenotype and its association with prognosis of paediatric inflammatory bowel disease in China.

BACKGROUND: To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. METHODS: We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn's disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. RESULTS: Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0-2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3-9 and 10-16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0-2 y and B3 phenotype; 0-2 y, B3 phenotype and steroid dependency were risk factors for early relapse. CONCLUSIONS: Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients.

Histologic lung cancer subtype differentiates synchronous multiple primary lung adenocarcinomas from intrapulmonary metastases.

BACKGROUND: Distinguishing synchronous multiple primary lung cancers (SMPLCs) from intrapulmonary metastases is important. The objective of this study was to determine long-term survival in patients who underwent surgical resection for synchronous multiple lung cancers and identify additional criteria that may be useful to distinguish patients with SMPLCs from those with more advanced disease. METHODS: The medical records of patients with lung cancer who underwent planned resection for synchronous multiple lung cancers from 2007 to 2012 at our institutions were reviewed retrospectively. A comprehensive histologic assessment was used to determine whether the tumors were metastases or separate synchronous primary tumors. RESULTS: A total of 51 patients with synchronous multiple lung cancers underwent surgical resection. Twenty-nine patients had ipsilateral synchronous multiple lung cancers, and 22 had bilateral synchronous multiple lung cancers. No perioperative death occurred. The survival analysis of all 51 patients with synchronous multiple lung cancers who underwent planned resection of all lesions showed 3- and 5-year overall survival rates of 86% and 67%, respectively, The median overall survival was not reached. The comprehensive histologic assessment identified six patients with intrapulmonary metastasis and 45 patients with SMPLCs. Intrapulmonary metastases were associated with decreased survival. Among patients with SMPLCs, the epidermal growth factor receptor mutation distribution shown high concordant frequency rate of 35% (5/14). CONCLUSIONS: Survival after surgical resection of synchronous multiple lung cancers in different lobes was promising. A comprehensive histologic assessment was useful for differentiating SMPLCs from intrapulmonary metastases.

Investigation of vitamin D status and its correlation with insulin resistance in a Chinese population.

OBJECTIVE: Although many studies worldwide have focused on the relationship between vitamin D and insulin resistance, results remain controversial. Furthermore, concentrations of serum 25-hydroxyvitamin D (25(OH)D) in the Chinese population are unclear. We aimed to investigate vitamin D status and its correlation with insulin resistance among a Chinese adult population. DESIGN: Serum 25(OH)D, fasting blood glucose, fasting insulin, glycated Hb (HbA1c) and other metabolic parameters were assessed. Neck circumference, waist circumference, hip circumference, weight and height were also measured. Lifestyle factors including smoking and drinking status were obtained. Diabetes mellitus was diagnosed by HbA1c according to the 2010 American Diabetes Association criteria. SETTING: Eastern China. SUBJECTS: Of 7200 residents included, 6597 individuals were ultimately analysed. RESULTS: We enrolled 2813 males (mean age 52·7 (sd 13·5) years) and 3784 females (52·3 (sd 13·5) years); mean serum 25(OH)D concentration was 43·1 (sd 11·6) and 39·6 (sd 9·8) nmol/l, respectively. Additionally, 83·3 % of participants were 25(OH)D deficient. A significant difference in 25(OH)D was observed between males and females in winter and spring (P<0·001). Furthermore, 25(OH)D concentrations were inversely associated with the homeostasis model assessment of insulin resistance (HOMA-IR) in the overweight and pre-diabetic populations. After adjusting for several variables, 25(OH)D was significantly associated with HOMA-IR in winter. When 25(OH)D values were categorized into quartiles, HOMA-IR was significantly associated with decreasing 25(OH)D. CONCLUSIONS: The majority of the Chinese population was vitamin D deficient and this deficiency was negatively associated with insulin resistance, particularly in the overweight and pre-diabetic populations. Moreover, these associations might be more evident in the winter.

Utility and safety of tolvaptan in cirrhotic patients with hyponatremia: A prospective cohort study.

Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free water excretion, but its efficacy and safety in cirrhotic patients remain unclear. MATERIAL AND METHODS: We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. RESULTS: Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). CONCLUSION: In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.

Increased Heme Oxygenase-1 and Nuclear Factor Erythroid 2-Related Factor-2 in the Placenta Have a Cooperative Action on Preeclampsia.

BACKGROUND: Previous studies have shown that oxidative stress is an important factor in preeclampsia (PE). Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor-2 (Nrf2) are protective proteins that are involved in combating oxidative stress in the body. Nrf2 is also an essential upstream transcription factor regulating HO-1. This study was aimed at exploring the physiological roles of HO-1 and Nrf2 in PE. METHODS: Serum and placenta were collected from 30 patients who presented with severe PE and 30 healthy pregnant females. HO-1 and Nrf2 levels in placenta were measured. Following stimulation of the HTR-8/SVneo cell line with tert-butylhydroquinone (tBHQ), an Nrf2 activator, nuclear Nrf2 protein and HO-1 mRNA levels were determined. RESULTS: Compared with the healthy pregnancy group, HO-1 protein and mRNA levels were increased in placental samples obtained from the severe PE group (p < 0.01, p < 0.05). Similar increases were also observed for Nrf2 protein levels (p < 0.01). Nuclear Nrf2 protein and HO-1 mRNA levels were both increased in the HTR-8/SVneo cell line following stimulation with tBHQ (p < 0.05). CONCLUSION: Patients with severe PE may be protected against oxidative injury following an elevation in HO-1 and Nrf2 levels. Nrf2 is likely to have a synergistic effect on HO-1 in PE.

Phase I trial of active specific immunotherapy with autologous dendritic cells pulsed with autologous irradiated tumor stem cells in hepatitis B-positive patients with hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma (HCC) is often associated with chronic hepatitis due to hepatitis-B or -C viruses. Active specific immunotherapy (ASI) with autologous dendritic cells (DC) presenting antigens from autologous tumor stem cell (TC) lines is associated with promising long-term survival in metastatic cancer, but hepatitis patients were excluded. ASI might benefit high-risk primary HCC patients following surgical resection, but first it is important to show that ASI does not exacerbate hepatitis. METHODS: Previously untreated HCC patients with a solitary lesion > 5 cm, or three lesions with at least one > 3 cm, or more than three lesions, underwent surgical resection from which autologous TC lines were established. Irradiated TC were incubated with autologous DC to create DC-TC. After one course of trans-arterial chemoembolization therapy (TACE), three weekly subcutaneous injections of DC-TC suspended in granulocyte-macrophage colony stimulating factor were administered. Patients were monitored for eight weeks. RESULTS: HCC cell lines were established within five weeks for 15/15 patients. Eight patients, all with chronic hepatitis B, were treated. There was no increase in hepatic transaminases, hepatitis B antigens, or viral DNA. CONCLUSION: Autologous DC-TC did not exacerbate HBV in these HCC patients. A phase II efficacy trial is being planned.

[Chemical exposure, leukemia related DNA methylation changes and childhood acute leukemia].

OBJECTIVE: To evaluate the association between chemical exposure, DNA methylation status and gene-environment interactions in the development of childhood acute leukemia (AL). METHODS: From January 1st 2009 to December 31st 2010, an exploratory case-control study was conducted on childhood AL among children who were less than 15 years of age in Shanghai, China. A total of 131 patients with newly diagnosed AL were recruited from 3 Shanghai children hospitals. The controls selected from the same hospital were healthy children who attended the physical check-up held by the department of Children's Healthcare, or who visited the clinic of developmental pediatrics or orthopedics (excluding blood diseases and malignant tumors). 140 controls matched with cases in gender and age were included in this study. Chemical exposure were investigated by questionnaires, methylation specific polymerase chain reaction (MSP) was adopted to analyze the methylation or deletion status of 8 genes, and gene-environment interactions were analyzed by relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index (S). RESULTS: There were 131 and 140 subjects in case and control group, who were aged (6.9 ± 3.8) and (6.9 ± 3.9) years old (t = 0.01, P = 0.911), respectively. After adjusting age and other potential confounding factors, chemical substances' exposure of children/mother/father were all significantly higher in cases than that in controls (Children: OR = 3.90, 95% CI: 1.69-9.02; Mother: OR = 2.71, 95% CI: 1.12-6.52; Father: OR = 1.91, 95% CI: 1.05-3.47). For the 8 genes analyzed, the methylation status of DAPK and PTEN and P73 in case group were significantly higher than that in control group (cases: 3.1% (4 cases), 16.0% (21 cases), 7.6% (10 cases); controls: 0.7% (1 case), 2.9% (4 cases), 0.7% (1 case); χ²: 7.11, 16.90, 11.38; P value: 0.029, 0.000, 0.003). The methylation status of P16 in case group was significantly lower than that in control group (cases: 3.8% (5 cases); controls: 8.6% (12 cases), χ² = 10.33, P = 0.007). The interactions of children chemical substances' exposure and 3 genes' (PTEN, P16 and P73) methylation status were probably existed after adjusted for confounding factors (PTEN: RERI = -7.01, API = -2.14, S = 0.24; P16: RERI = 4.08, API = 0.53, S = 2.59; P73: RERI = 4.32, API = 0.48, S = 2.19), we also found the potential interaction between maternal chemical substances' exposure and PTEN, P16 gene methylation status (PTEN: RERI = -1.30, API = -0.38, S = 0.65; P16: RERI = 1.70, API = 0.38, S = 1.97). CONCLUSION: The study suggested the strong combined effects of chemical substances exposure of children and abnormal methylation status were risk factors of childhood AL, and there existed different interaction between them, which may indicate the important role in the pathogenesis process of childhood AL.