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Printed cutting and repositioning templates could bring superior accuracy when transferring a maxillary plan to the operating room compared to a wafer-based method. However, the effect of these methods in different types of cases is inconclusive. The objective of the study was to compare the accuracy when using printed occlusal splints versus templates in simple and complicated cases.A retrospective cohort study design was used. Complicated cases were defined as cases involving impaction movement of more than 2 mm, occlusal plane canting of more than 3°, or midline discrepancies of more than 2.5 mm. Other cases were simple cases. Enrolled patients were randomly allocated into the digital occlusal splint (DOS) cohort and the digital templates (DT) cohort. The outcome variable was surgical accuracy, defined as the average deviation between the planned and postsurgical locations of bilateral maxillary central incisors, canines, first premolars, and first molars. Predictor variables were 1) operative complexity, simple versus complicated; and 2) technique for positioning the maxilla, DOS versus DT. Covariates were age and planned surgical movement. Two-way analysis of variance was used.Seventy patients were included in this study. Thirty-three were in the DOS cohort, and 37 in the DT cohort. The average deviation was significantly smaller in the complicated cases in the DT cohort (1.37 mm; 95% confidence interval, 1.08-1.66 mm) than that in the DOS cohort (2.47 mm; 95% confidence interval, 1.92-3.02 mm) (P = .002). The deviations in anteroposterior direction of complicated cases in the DT cohort were smaller than the corresponding values of the DOS cohort (P = .035). There is no significant difference between the deviation values of simple and complicated cases using templates (P = .116).These results indicate that in complicated cases, printed guiding templates exhibit better accuracy for repositioning the maxilla than printed occlusal splints, and the effect of templates in different cases proved to be stable.

The COVID-19 infection adversely affects the cardiovascular system. Transthoracic echocardiography has demonstrated diagnostic, prognostic and therapeutic utility. We report biventricular myocardial strain in COVID-19. Methods: Biventricular strain measurements were performed for 12 patients. Patients who were discharged were compared with those who needed intubation and/or died. Results: Seven patients were discharged and five died or needed intubation. Right ventricular strain parameters were decreased in patients with poor outcomes compared with those discharged. Left ventricular strain was decreased in both groups but was not statistically significant. Conclusion: Right ventricular strain was decreased in patients with poor outcomes and left ventricular strain was decreased regardless of outcome. Right ventricular strain measurements may be important for risk stratification and prognosis. Further studies are needed to confirm these findings.

As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and neuropathy. However, the drug development of CX3CR1 is hampered partially by the lack of structural information. Here, we present two cryo–electron microscopy structures of CX3CR1-G i1 complexes in ligand-free and CX3CL1-bound states at 2.8- and 3.4-Å resolution, respectively. Together with functional data, the structures reveal the key factors that govern the recognition of CX3CL1 by both CX3CR1 and US28. A much smaller conformational change of helix VI upon activation than previously solved class A GPCR-G i complex structures is observed in CX3CR1, which may correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling transduction. Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein–coupled receptor) signaling and provide insights into the diversity of G protein coupling.

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder featured by memory loss and cognitive default. However, there has been no effective therapeutic approach to prevent the development of AD and the available therapies are only to alleviate some symptoms with limited efficacy and severe side effects. Necroptosis is a new kind of cell death, being regarded as a genetically programmed and regulated pattern of necrosis. Increasing evidence reveals that necroptosis is tightly related to the occurrence and development of AD. This review aims to summarize the potential role of necroptosis in AD progression and the therapeutic capacity of targeting necroptosis for AD patients.

This study aims to show our institute’s experience in the treatment of HH and its associated facial deformities in adults and growing adolescents and to investigate condylar remodeling and volumetric changes and long-term stability of orthognathic surgery in adults. The study included consecutive patients with clinical and radiological features of HH who underwent high condylectomy with or without simultaneous orthognathic surgery from 2013 to 2018. The clinical outcomes were assessed based on functional activities, TMJ pain, and recurrence. Postoperative 3D condylar remodeling and orthognathic stability were evaluated with the use of ITK-Snap and 3D Slicer. Thirteen patients (8 females and 5 males) with a mean age of 26.3 ± 5.79 years (range; 13–34 years) were included with facial asymmetry as the chief complaint. The patients were followed up for a minimum of 12 months and a maximum of 4 years (mean; 16.85 ± 10.04). There were no postoperative complications, and all patients achieved a satisfactory functional and aesthetic outcome using a one-stage surgical procedure. There was no incidence of recurrence or further asymmetries, with long-term stability at the selected points showing a mean difference of less than ±1 mm. The affected condylar volume was significantly reduced following high condylectomy, with mean changes between T1 and T2 of −144. 80 mm3 (p = .012). However, the contralateral condylar volume remained stable, with a mean change of 2.54 mm3 (p = .881). One-stage high condylectomy and orthognathic surgery is a viable measure for the treatment of HH and associated deformities in adults. High condylectomy in early adolescence could result in termination of the disease, and aesthetic improvement with further constant orthodontist-surgeon follow-up is required.

Aim. To investigate whether vitamin C performs well as a supplemental treatment for common cold.Method. After systematically searching through the National Library of Medicine (PubMed), Cochrane Library, Elsevier, China National Knowledge Infrastructure (CNKI), VIP databases, and Wanfang databases, 10 randomized controlled trials were selected for our meta-analysis with RevMan 5.3 software. Published in China, all 10 studies evaluated the effect of combined vitamin C and antiviral therapy for the treatment of common cold.Results. The total efficacy (RR=1.27, 95% CI (1.08, 1.48),P=0.003), the time for symptom amelioration (MD=−15.84, 95% CI (-17.02, -14.66),P<0.00001), and the time for healing (I, 95% CI (-14.98, -4.22),P=0.0005) were better with vitamin C supplementation than with antiviral therapy alone.Conclusions. Vitamin C could be used as a supplementary therapy along with antiviral regimens to relieve patients from the symptoms of common cold.

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Metabolic dysfunction plays a key role in the development of diabetic nephropathy (DN). However, the exact effects and mechanisms are still unclear. The pyrin domain-containing protein 3 (NLRP3) inflammasome, a member of the nod-like receptor family, is considered a crucial inflammatory regulator and plays important roles in the progress of DN. A growing body of evidence suggests that high glucose, high fat, or other metabolite disorders can abnormally activate the NLRP3 inflammasome. Thus, in this review, we discuss the potential function of abnormal metabolites such as saturated fatty acids (SFAs), cholesterol crystals, uric acid (UA), and homocysteine in the NLRP3 inflammasome activation and explain the potential function of metabolic dysfunction regulation of NLRP3 activation in the progress of DN via regulation of inflammatory response and renal interstitial fibrosis (RIF). In addition, the potential mechanisms of metabolism-related drugs, such as metformin and sodium glucose cotransporter (SGLT2) inhibitors, which have served as the suppressors of the NLRP3 inflammasomes, in DN, are also discussed. A better understanding of NLRP3 inflammasome activation in abnormal metabolic microenvironment may provide new insights for the prevention and treatment of DN.

The aim of this study is to investigate the effect of bimaxillary orthognathic surgery on orofacial myofunctional changes in skeletal class III patients. 35 patients who received Le Fort I maxillary advancement osteotomy and mandibular SSRO setback were included in this study. Facial expression function was analyzed by "placid" or "smile" expressions using chL-chR, ∠chRnchL, and ls-li. Occlusal force and balance were analyzed using a T-scan III digital occlusal analysis system. Maximum mouth opening (MMO) was measured prior to surgery and 2/14/28/42/90/180/360 days after surgery. After surgery, patients recovered facial expressions in no less than 3 months for both the "placid" or "smile" facial expression. Patients obtained significantly improved 'smile' expressions 3 months after the operation compared to preoperative "smiles", and this improvement remained stable 12 months after the operation. Occlusal force was significantly decreased with the balance of occlusion lost immediately after surgery. These conditions gradually recovered, and patients finally obtained a more balanced and stronger occlusion [occlusion balance: 6.7 ± 2.7 mm vs. 4.1 ± 3.0 mm (day -7 vs. day 42); occlusion force: 19.6 ± 7.0 kg vs. 24.2 ± 9.3 kg (day -7 vs. day 180)]. However, patients had smaller postoperative mouth opening compared to preoperation opening during our follow-up. Our results confirmed that orthognathic surgery obstructs orofacial myofunctions of skeletal class III patients in the short-term. In the long-term, orthognathic surgery results in more stable and balanced orofacial myofunctions. By understanding the process of functional recovery of orofacial muscles after orthognathic surgery, we hope to accelerate patient's recovery from surgery.

Background Tracheostomy and endotracheal intubation can result in subglottic tracheal stenosis, and predisposition to keloid scar formation can increase stenosis risk after tracheal injury. This study aims to compare the incidence and severity of subglottic tracheal stenosis in keloid and non‐keloid patients following iatrogenic tracheal injury, in particular tracheostomy. Methods From 2012 to 2017, 218 573 patients were intubated for surgery; 2276 patients received tracheostomy in People’s Hospital of Zhengzhou University, China. Among these patients, 133 patients, who developed tracheal stenosis after intubation and/or tracheostomy, were divided into keloid or non‐keloid groups; their Myer and Cotton grading of tracheal stenosis, time‐to‐onset of airway stenosis, and treatment outcome were assessed and compared. Results The percentages of high grade (Myer and Cotton grading III/IV) tracheal stenosis were higher among keloid patients than non‐keloid patients (intubation: 83.3% vs 25.7%; tracheostomy: 77.7% vs 33.3%). Time‐to‐onset of airway stenosis following intubation (tracheostomy) was 27 ± 5 (38 ± 13) and 41 ± 7 (82 ± 14) days for keloid and non‐keloid patients, respectively (P

COVID-19 infection can affect the cardiovascular system. We sought to determine if left ventricular global longitudinal strain (LVGLS) is affected by COVID-19 and if this has prognostic implications. Materials & methods: Retrospective study, with LVGLS was measured in 58 COVID-19 patients. Patients discharged were compared with those who died. Results: The mean LV ejection fraction (LVEF) and LVGLS for the cohort was 52.1 and -12.9 ± 4.0%, respectively. Among 30 patients with preserved LVEF(>50%), LVGLS was -15.7 ± 2.8%, which is lower than the reference mean LVGLS for a normal, healthy population. There was no significant difference in LVGLS or LVEF when comparing patients who survived to discharge or died. Conclusion: LVGLS was reduced in COVID-19 patients, although not significantly lower in those who died compared with survivors., Lay abstract COVID-19 infection can affect the cardiovascular system including the heart muscle. Myocardial strain measures the function of the heart muscle at cell level and can pick up unusual heart function before routine measurements. Ejection fraction (how hard the heart muscle is squeezing) can be seen with our own eyes, but strain cannot and needs special techniques to see it. In this study we wanted to find out what was the strain on COVID-19 patients and if there was a relationship between strain and the outcome of the patients (if they were able to recover from COVID-19). The important finding of our study is that strain was low in all patients with COVID-19 infection regardless of routine measurements when compared with patients without the infection. However, in this study we found no correlation between the low strain and the result of the infection for the COVID-19 patients.

Background: The relationship between cancer with body mass index has been extensively reported. However, association between urinary cancers with these risk factors remains unclear, with existing reports showing conflicting findings. The current review, therefore, sought to clarify the latter association by assessing the methodological and reporting quality of existing systematic reviews on the subject. Methods: We will screen PubMed, EMBASE, and Cochrane Library databases for relevant literature and subjected the resulting articles to meta-analysis. We will adopt the AMSTAR and PRISMA checklists for assessing methodological, and reporting quality, respectively. The association between BMI and different urinary cancers will be estimated by computing the pooled relative risk (RR) and its 95% confidence interval (CI), which will be calculated from the adjusted RR, odds ratio, or hazard ratio, and 95% CI offered in the studies. Heterogeneity between studies will be assessed with the I statistic as a measure of the proportion of total variation in estimates that is due to heterogeneity, where I values of 25%, 50%, and 75% correspond to cut-off points for low, moderate, and high degrees of heterogeneity. The random effects model will be used as the pooling method when significant heterogeneity existed and the fixed effect model will be used when no heterogeneity was observed. Possible publication bias will be tested by Begg and Egger test. Conclusion: Our evidence synthesis will provide a new commentary on the current systematic review evidence for the association between BMI and the risk of different urinary cancers. PROSPERO registration number: CRD42019119459.

The human neuropeptide Y (NPY) Y2 receptor (Y2R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y2R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y2R bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details of the ligand-binding mode of Y2R. Combined with mutagenesis studies, the Y2R structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound Y1R structures identified receptor-ligand interactions that play different roles in modulating receptor activation and mediating ligand selectivity. These findings deepen our understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors, and would enable structure-based drug design., The human neuropeptide Y receptor Y2 (Y2R) is a drug target for the treatment of obesity and anxiety. Crystal structure of Y2R bound to a selective antagonist and accompanying mutagenesis provide insights into ligand recognition and subtype specificity of NPY receptors.

This study aimed to evaluate whether ultrasound-guided techniques are superior compared to traditional palpation techniques in patients undergoing radial artery catheterization (RAC).Electronic databases of PubMed, Embase, and the Cochrane Library were systematically searched to identify randomized controlled trials (RCTs). The relative risks (RRs) or weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) were used to calculate the pooled effect estimates using the random effects model for categories and continuous data, respectively.A total of 19 RCTs comprising a total of 3220 individuals were selected for final analysis. The pooled RR suggested that ultrasound-guided techniques were associated with higher incidence of first attempt success than traditional palpation techniques (RR, 1.39; 95% CI, 1.21-1.59; P 0.001). Moreover, we noted that ultrasound-guided techniques were associated with fewer mean attempts to success (WMD, -0.80 s; 95% CI, -1.35 to -0.25; P = 0.004) and a shorter mean time to success (WMD, -41.18 s; 95% CI, -75.43 to -6.93; P = 0.018) than traditional palpation techniques. Furthermore, individuals using ultrasound-guided techniques had a reduced risk of hematoma (RR, 0.40; 95% CI, 0.22-0.72; P = 0.003).This study indicated that ultrasound-guided techniques were superior compared to traditional palpation techniques for RAC in terms of efficacy and complications.

Background/Aims: Chemotherapy is still the main strategy used to prevent the relapse of acute myeloid leukaemia (AML). As the most abundant stromal component in bone marrow (BM), marrow adipocytes have been previously shown to promote leukaemogenesis. The present study was designed to further validate whether marrow adipocytes exert synergistic effects on strengthening chemotherapeutic efficacy and evaluate the underlying mechanism. Methods: A retrospective study of BM biopsies from 80 patients with AML in remission and 71 control subjects was applied to quantitatively analyse the marrow adipocyte volume. Toxicity tests were used to assess the effect of chemotherapy drugs on BM cells. The possible mechanisms by which chemotherapy regulated the reduced marrow adipocyte content were investigated using antibody neutralization experiments, with an emphasis on growth differentiation factor 15 (GDF15). Results: In our study, the marrow adipocyte content was obviously reduced in the AML- complete remission (CR) group compared with the control group (P

Sodium (Na+) channels are the basis for action potential generation and propagation, which play a key role in the regulation of neuronal excitability. SCN3A is a gene encoding for sodium channel protein type 3 subunit alpha (or known as Nav1.3). This study aimed to explore SCN3A genetic variants in a cohort of childhood absence epilepsy (CAE) via whole exome sequencing. A novel SCN3A missense variant (c.A1816G, p.Ser606Gly) was identified in a patient with CAE. This variant had not been reported in both 1000G and ExAC databases. Bioinformatics analysis revealed that this variant was pathogenic and could transform the protein structure of Nav1.3. The reported phenotypes of SCN3A-related central nerve system disorders included multiple seizure types, polymicrogyria and different degrees of developmental delay/intellectual disability. The patient with p.Ser606Gly variant exhibited typical absence seizures. The MRI and CT scan results were normal, and EEG showed that 3-Hz spike-slow wave discharges. In conclusion, our findings not only broaden the pathogenic spectrum of SCN3A, but also extend the clinical phenotypes of SCN3A-related CAE.

Background Xingnao Kaiqiao acupuncture involves needling of the Neiguan (PC6), Renzhong (DU26), and Sanyinjiao (SP6) acupoints. The technique has a significant clinical effect in many neurological diseases. In the present report, we have developed a protocol for a scientific trial to analyze whether Xingnao Kaiqiao can be used to treat gastrointestinal dysfunction after laparoscopic surgery. In this context, we intend to execute a double-blind, randomized controlled trial to assess the efficacy and safety of Xingnao Kaiqiao acupuncture via intradermal needling. Methods/design This will be a single-center, double-blind, randomized controlled clinical trial. It has been designed on the basis of the Consolidated Standards of Reporting Trials (CONSORT 2010) guidelines and the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA). The subjects will be recruited from among inpatients scheduled for laparoscopic surgery at the Department of Minimally Invasive Surgery, Tianjin Nankai Hospital, Tianjin, China. Using random numbers generated in SPSS 19.0, the recruited subjects will be allocated to either the “Xingnao Kaiqiao” group or the sham stimulation group. A specially appointed investigator will be in charge of the randomization. Xingnao Kaiqiao via intradermal needling (or sham needling) will be administered 6 h after laparoscopic surgery, and then every 12 h for a total of six sessions, each of which will last 3 min. The subjects will undergo their first evaluation shortly before the first treatment (6 h after laparoscopic surgery); evaluations will be repeated every 12 h until a total of seven evaluations have been completed. The primary outcome will be the time until the first postoperative flatus. The secondary outcomes will be: the time until the first postoperative defecation; levels of abdominal pain, abdominal distension, and nausea; blood ghrelin level; occurrence of vomiting; psychological status; and quality of life. Discussion This upcoming randomized clinical trial was designed as a standardized method to assess the efficacy and safety of Xingnao Kaiqiao acupuncture using intradermal needles on PC6, DU26, and SP6 in the treatment of gastrointestinal dysfunction after laparoscopic surgery. We aim to provide evidence and thus improve the clinical application of this technique. Trial registration Chinese Clinical Trial Registry, ChiCTR-IOR-17010763. Registered on 2 March 2017. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2319-3) contains supplementary material, which is available to authorized users.

Background Primary dysmenorrhoea (PD), defined as painful menses in women with normal pelvic anatomy, is one of the most common gynaecological syndromes. Acupoint-stimulation could potentially be an effective intervention for PD. Our aim was to determine the effectiveness of acupoint-stimulation compared with Non-Steroidal Anti-Inflammatory Drugs (NASIDs) in the treatment of PD. Methods Six databases were searched to December 2014. Sixteen studies involving 1679 PD patients were included. We included randomized controlled trials that compared acupoint-stimulation with NASIDs for the treatment of PD. The main outcomes assessed were clinical effectiveness rate, symptom score, visual analogue score, variation in peripheral blood prostaglandin F2α (PGF2α) and side effects. All analyses were performed using Comprehensive Meta-Analysis statistical software. Results (1) The total efficacy was better than control group: odds ratio = 5.57; 95% confidence interval (95% CI) = 3.96, 7.83; P

Endometriosis has many hypothesized etiologies. Known risk factors include genetic predisposition, uterine outflow abnormalities, and iatrogenic causes. Of increasing concern is prenatal environmental exposures. However, the findings of studies investigating the relationships between prenatal environmental exposures and the development of endometriosis have not always been conclusive, and therefore, the relationships are debatable. This review presents a summary and analysis of the current studies that investigated the effects of prenatal environmental exposures on the development of endometriosis in female offspring. Prenatal exposureto estrogenic substances (such as ethinyl estradiol and diethylstilbestrol) and environmental toxins (such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyls, and bisphenol A) may increase the incidence of endometriosis in female offspring. However, exposure to cigarette smoke may protect againstthe development of endometriosis in female offspring mainly because of its antiestrogenic effects. Certain prenatal environmental exposures might result in the development of endometriosis in female offspring. In addition to known environmental exposures that predispose the development of endometriosis in adulthood, such as dioxin and radiation exposure (animal modeis), prenatal exposures are of increasing concern.

Wearable electrochemical biosensors for sweat analysis present a promising means for noninvasive biomarker monitoring. However, sweat-based sensing still poses several challenges, including easy degradation of enzymes and biomaterials with repeated testing, limited detection range and sensitivity of enzyme-based biosensors caused by oxygen deficiency in sweat, and poor shelf life of sensors using all-in-one working electrodes patterned by traditional techniques (e.g., electrodeposition and screen printing). Herein, a stretchable, wearable, and modular multifunctional biosensor is developed, incorporating a novel MXene/Prussian blue (Ti3 C2 Tx /PB) composite designed for durable and sensitive detection of biomarkers (e.g., glucose and lactate) in sweat. A unique modular design enables a simple exchange of the specific sensing electrode to target the desired analytes. Furthermore, an implemented solid-liquid-air three-phase interface design leads to superior sensor performance and stability. Typical electrochemical sensitivities of 35.3 µA mm-1 cm-2 for glucose and 11.4 µA mm-1 cm-2 for lactate are achieved using artificial sweat. During in vitro perspiration monitoring of human subjects, the physiochemistry signals (glucose and lactate level) can be measured simultaneously with high sensitivity and good repeatability. This approach represents an important step toward the realization of ultrasensitive enzymatic wearable biosensors for personalized health monitoring.

A 38-year-old man with a history of resistant hypertension for more than 10 years underwent laparoscopic-based perivascular unilateral renal sympathetic nerve denervation in 2012. After the operation, the patient’s blood pressure has been controllable while the antihypertensive drug intake has decreased over 6 years. Laparoscopic-based perivascular unilateral renal sympathetic nerve denervation may be a potentially feasible and effective option in treating patients with resistant hypertension.

Autoimmune hemolytic anemia (AIHA) is a rare disease in children, and its clinical severity varies. To better understand disease manifestation and treatment outcome, we analyzed 68 children diagnosed as AIHA for clinical characteristics, laboratory findings, and treatment outcomes. Data show that primary AIHA accounted for 39.7% of all patients, whereas secondary AIHA accounted for 60.3%. Among them, Evans syndrome (ES) accounted for 20 cases (29.4%). Average hemoglobin was lower in the 1-year or below age group than in the above 1-year age group, combined-antibody group than single-antibody group, and IgM-contained group than non-IgM-contained group (P

The present study aimed to explore the function of miR‑34b promoter methylation in cell proliferation in children's acute leukemia. Quantitative PCR and methylation‑specific PCR were performed to measure the levels of miR‑34b and its promoter methylation in normal cells, eight leukemia cell lines as well as primary leukemic cells isolated from patients newly diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and mixed lymphocytic lymphoma. miR‑34b levels in leukemia cell lines and primary leukemic cells were significantly lower than those in normal cells. The miR‑34b promoter was found to be methylated in all leukemia cell lines, 24 of 31 ALL patients and 8 of 19 AML patients, but not in the 23 normal controls. miR‑34b expression and methylation of its promoter were not associated with most clinical parameters assessed; however, miR‑34b levels in prednisone‑sensitive ALL were significantly different from those in insensitive ALL. A cell counting kit‑8 assay showed that transfection of miR‑34b mimics into K562 cells inhibited their proliferation. Furthermore, treatment with the demethylating agent 5‑aza‑2‑deoxycytidine significantly enhanced miR‑34b expression levels and decreased the methylation status of its promoter in HL‑60 and K562 cells. In conclusion, the results of the present study indicated that in pediatric leukemia cells and leukemia cell lines, the expression of miR‑34b is inhibited by methylation of its promoter, which impairs the restraining effects of miR‑34b on cell proliferation. It was also indicated that the expression of miR‑34b in ALL patients may affect their response to early treatments.

Autophagy is required for hematopoietic stem cell multilineage differentiation, but the underlying mechanism is unknown. Using a conditional mouse model and human leukemia cells, we uncovered a mechanistic link between autophagy and hematopoietic stem cell differentiation. Loss of autophagy in mouse hematopoietic stem cells diminished the bone marrow generation of functional blood cells, in particular lymphocytes, and resulted in a leukemic phenotype and elevated Notch signaling. Physiological autophagy activity in mice was inversely correlated with Notch signaling during adult hematopoietic stem cell differentiation, while pathologically low autophagy was associated with upregulated Notch signaling in dysfunctional hematopoietic stem cells of acute leukemia patients. Furthermore, we show that autophagy directly degraded intracellular Notch, the active form of Notch receptor cleaved from the full-length Notch molecule by γ-secretase. Finally, we show that hematopoietic multilineage differentiation potential was restored in autophagy defective hematopoietic stem and progenitor cells when their Notch signaling was abrogated either pharmacologically with γ-secretase inhibitor DAPT or genetically with RNA interference of Notch effector RBPJ. Hence, we propose that autophagy sustains hematopoiesis by direct targeting Notch.

Background HPV 18 is one of the most prevalent oncogenic types, only second to HPV 16, and included in the licensed vaccines on the market. In this study, we describe the production and characterization of a panel of monoclonal antibodies (mAb) to HPV18. Methods The immunocompetence of 1B1 and 4C2 mAbs for HPV L1 protein was evaluated by SDS-PAGE analysis, neutralization assays, affinity identification, and ELISA. The 1B1 and 4C2 genes were sequenced and analyzed. Finally, the detection kit with the two mAbs was assessed for linearity, repeatability and specificity. Results Both mAbs specifically recognized HPV18 L1 and virus-like particles (VLPs). These mAbs are conformation-neutralizing antibodies that have high affinity and type specificity. Based on these characteristics of these mAbs, we developed an ELISA kit for specifically detecting HPV 18 antigen. We showed that this kit displayed good linearity, repeatability and sensitivity for detecting HPV18 L1 pentamer and HPV18 VLP. Conclusions We characterized two monoclonal neutralizing antibodies for HPV L1 protein, and developed an ELISA kit for specifically detecting HPV 18 antigen. This newly developed kit can be used to monitor the potency of HPV vaccines throughout the entire production process as well as preliminary analysis of HPV18 infections.

Aim. To investigate whether vitamin C is effective in the treatment of the common cold.Method. After systematically searching the National Library of Medicine (PubMed), Cochrane Library, Elsevier, China National Knowledge Infrastructure (CNKI), VIP databases, and WANFANG databases, 9 randomized placebo-controlled trials were included in our meta-analysis in RevMan 5.3 software, all of which were in English.Results. In the evaluation of vitamin C, administration of extra therapeutic doses at the onset of cold despite routine supplementation was found to help reduce its duration (mean difference (MD) = -0.56, 95% confidence interval (CI) [-1.03, -0.10], and P = 0.02), shorten the time of confinement indoors (MD = -0.41, 95% CI [-0.62, -0.19], and P = 0.0002), and relieve the symptoms associated with it, including chest pain (MD = -0.40, 95% CI [-0.77, -0.03], and P = 0.03), fever (MD = -0.45, 95% CI [-0.78, -0.11], and P = 0.009), and chills (MD = -0.36, 95% CI [-0.65, -0.07], and P = 0.01).Conclusions. Extra doses of vitamin C could benefit some patients who contract the common cold despite taking daily vitamin C supplements.

Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor, however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35, p &lt, 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy, however, the underlying mechanisms remain to be determined.

For children with precursor B (pre-B) acute lymphoblastic leukemia (ALL) with TCF3-PBX1 fusion gene, their prognosis has been a controversial topic. From January 2008 to December 2012 in our hospital, 450 patients were diagnosed as ALL. Clinical characteristics of 20 patients with TCF3-PBX1 fusion gene were analyzed retrospectively, which were classified to the intermediate-risk (IR) group according to Chinese Children Leukemia Group-2008 (CCLG-2008) risk-stratification criteria and protocol based on the backbone of BFM 95 trails. Eighty five cases without TCF3-PBX1 in the same IR group were regarded as the comparison group. There were no differences in age, gender, initial white blood cell (WBC) count, status of central nerves system (CNS) at diagnosis and complete remission (CR) rates of bone marrow (BM) between the two groups (P.05). The 5-year probability of event-free survival (EFS) rates were 84.4 ± 15.6% and 73.5 ± 15.6% in the TCF3-PBX1 group and the comparison group (P = .35), respectively. The 5-year probability of overall survival (OS) rates were 86.0 ± 17.6% and 81.8 ± 17.6% (P = .46), respectively. Relapse rates were 10.5% and 12.9% (P = 1.00), respectively. There were not cases with CNS relapse in the TCF3-PBX1 group. When intensive chemotherapy was used, the TCF3-PBX1 was associated with a favorable outcome in childhood pre-B ALL.

B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia.

Background: Contrast-enhanced ultrasound (CEUS) is considered a novel method for diagnosing pancreatic cancer, but currently, there is no conclusive evidence of its accuracy. Using CEUS in discriminating between pancreatic carcinoma and other pancreatic lesions, we aimed to evaluate the diagnostic accuracy of CEUS in predicting pancreatic tumours. Methods: Relevant studies were selected from the PubMed, Cochrane Library, Elsevier, CNKI, VIP, and WANFANG databases dating from January 2006 to May 2017. The following terms were used as keywords: “pancreatic cancer” OR “pancreatic carcinoma,” “contrast-enhanced ultrasonography” OR “contrast-enhanced ultrasound” OR “CEUS,” and “diagnosis.” The selection criteria are as follows: pancreatic carcinomas diagnosed by CEUS while the main reference standard was surgical pathology or biopsy (if it involved a clinical diagnosis, particular criteria emphasized); SonoVue or Levovist was the contrast agent; true positive, false positive, false negative, and true negative rates were obtained or calculated to construct the 2 × 2 contingency table; English or Chinese articles; at least 20 patients were enrolled in each group. The Quality Assessment for Studies of Diagnostic Accuracy was employed to evaluate the quality of articles. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, summary receiver-operating characteristic curves, and the area under curve were evaluated to estimate the overall diagnostic efficiency. Pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio with 95% confidence intervals (CIs) were calculated with fixed-effect models. Results: Eight of 184 records were eligible for a meta-analysis after independent scrutinization by 2 reviewers. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratios were 0.86 (95% CI 0.81–0.90), 0.75 (95% CI 0.68–0.82), 3.56 (95% CI 2.64–4.78), 0.19 (95% CI 0.13–0.27), and 22.260 (95% CI 8.980–55.177), respectively. The area under the SROC curve was 0.9088. Conclusion: CEUS has a satisfying pooled sensitivity and specificity for discriminating pancreatic cancer from other pancreatic lesions.

Background Endometriosis is a multifactorial, oestrogen-dependent, inflammatory, gynaecological condition that can result in long-lasting visceral pelvic pain and infertility. Acupuncture could be an effective treatment for endometriosis and may relieve pain. Our aim in the present study was to determine the effectiveness of acupuncture as a treatment for endometriosis-related pain. Methods In December 2016, six databases were searched for randomised controlled trials that determined the effectiveness of acupuncture in the treatment of endometriosis-related pain. Ultimately, 10 studies involving 589 patients were included. The main outcomes assessed were variation in pain level, variation in peripheral blood CA-125 level, and clinical effective rate. All analyses were performed using comprehensive meta-analysis statistical software. Results Of the 10 studies included, only one pilot study used a placebo control and assessed blinding; the rest used various controls (medications and herbs), which were impossible to blind. The sample sizes were small in all studies, ranging from 8 to 36 patients per arm. The mean difference (MD) in pain reduction (pre- minus post-interventional pain level—measured on a 0–10-point scale) between the acupuncture and control groups was 1.36 (95% confidence intervals [CI] = 1.01–1.72, P

Rapamycin has been shown to inhibit the growth of leukemic cells via an unknown mechanism. In our current study, we show that rapamycin activates autophagy in pediatric t(1;19) pre-B acute lymphoblastic leukemia (pre-B ALL) cells and thereby inhibits proliferation and induces growth arrest in these cells. Rapamycin was found to downregulate an extensive array of positive cell cycle regulators, reduce the total DNA and RNA levels, and specifically downregulate the gene transcription of DNA pol δ1 and RNA pol II. Furthermore, we show that both rapamycin and starvation caused a downregulation of the DNA pol δ1 and RNA pol II proteins which was reversed by the autophagy inhibitor 3-MA. Consistent with the results of our autophagic flux analysis, confocal microscopy indicated that both rapamycin and starvation cause the colocalization of DNA pol δ1 and RNA pol II with GFP-LC3 at autophagosomes. This colocalization was blocked by the autophagy inhibitor bafilomycin A1 which inhibits the fusion between autophagosomes and lysosomes. These data suggest that rapamycin inhibits the growth of pediatric t(1;19) pre-B ALL cells through both transcriptional inhibition and autophagic degradation of DNA pol δ1 and RNA pol II.

Despite its dual role in determining cell fate in a wide array of solid cancer cell lines, autophagy has been robustly shown to suppress or kill acute myeloid leukemia cells via degradation of the oncogenic fusion protein that drives leukemogenesis. However, autophagy also induces the demise of acute leukemia cells that do not express the known fusion protein, though the molecular mechanism remains elusive. Nevertheless, since it can induce cooperation with apoptosis and differentiation in response to autophagic signals, autophagy can be manipulated for a better therapy on acute myeloid leukemia.

Background Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature of AML. GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear. Methods Transcriptional expression levels of GATA4 were evaluated by semi-quantitative and real-time PCR. Methylation status was investigated by methylation-specific PCR (MSP) and bisulfate genomic sequencing (BGS). The prognostic significance of GATA4 expression and promoter methylation was assessed in 105 cases of Chinese pediatric acute myeloid leukemia patients with clinical follow-up records. Results MSP and BGS analysis showed that the GATA4 gene promoter is hypermethylated in AML cells, such as the HL-60 and MV4-11 human myeloid leukemia cell lines. 5-Aza treatment significantly upregulated GATA4 expression in HL-60 and MV4-11 cells. Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples. GATA4 transcript levels were significantly decreased in AML patients (33.06 ± 70.94; P = 0.011) compared to normal bone marrow/idiopathic thrombocytopenic purpura controls (116.76 ± 105.39). GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031). Kaplan-Meier survival analysis revealed significantly shorter overall survival time in patients with GATA4 promoter methylation (P = 0.014). Conclusions Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples; our study implicates GATA4 as a putative tumor suppressor gene in pediatric AML. In addition, our findings imply that GATA4 promoter methylation is correlated with WBC and MRD. Kaplan-Meier survival analysis revealed significantly shorter overall survival in pediatric AML with GATA4 promoter methylation but multivariate analysis shows that it is not an independent factor. However, further research focusing on the mechanism of GATA4 in pediatric leukemia is required. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1760-5) contains supplementary material, which is available to authorized users.

The hepatic fibrogenesis and sexual dimorphism of hepatitis B virus-related liver cirrhosis (HBV-LC) are related to estrogen and its receptors. Abnormal expression of estrogen receptor α (ESR1) is implicated in the development of cirrhosis in both animal models and humans. Here, we examine whether the ESR1 polymorphisms are related to HBV-LC risk among chronic HBV carriers, and we investigate the functional significance of positively associated polymorphisms. A total of 2,404 unrelated Chinese HBV carriers were recruited to conduct the two-stage designed case-control study. Two ESR1 haplotype tagging polymorphisms, c.30T>C (rs2077647) and c.453-397T>C (rs2234693), were genotyped in 1,285 patients with HBV-LC and in 1,119 asymptomatic HBV carriers. We observed a significantly increased susceptibility to HBV-LC associated with the c.30C allele (P = 4.2 × 10(-8) ), c.453-397C allele (P = 2.0 × 10(-8) ), and [c.30C; c.453-397C] haplotype (Dominant model, P = 8.85 × 10(-10) , odds ratio = 1.50, 95% CI 1.32∼1.71) compared with the T alleles and (c.30T; c.453-397T) haplotype of c.30T>C and c.453-397T>C polymorphisms, respectively. Functional analyses were conducted to verify the biological functions of the associated genetic variations and showed that the c.453-397T>C polymorphism is a novel c.453-397C allele-specific and c-myb-dependent enhancer-like cis-acting regulatory variation and could be part of the genetic variations underlying the susceptibility of individuals to HBV-LC.

The T-box transcription factor T-bet is a key regulator for the lineage commitment in CD4 Th1 cells and CD8 T cells by activating the hallmark production of interferon-γ, and its expression level is linked to autoimmune diseases. T-1993C and T-1514C polymorphisms in the TBX21 gene (encoding T-bet) promoter can affect transcription activity. We investigated the distributions of these functional polymorphisms in 84 adult patients with type 1 autoimmune hepatitis (AIH-1) and 318 healthy controls. Intracellular T-bet staining of polarized CD4 Th1 cells from healthy controls corresponding to T-1993C genotypes were analyzed by flow cytometry. The -1993C allele frequency was 3.0% in AIH-1 and 11.8% in controls (p = 0.000 25). Individuals carrying the -1993C allele had a decreased risk to AIH-1 compared with those without the -1993C allele (p = 0.0016, odds ratio [OR] = 0.22, 95% confidence interval = 0.09-0.56). No association was found between the T-1514C polymorphism and AIH-1. The onset age of AIH-1 was also accelerated among -1993TT homozygotic individuals (p = 0.013). The fractions of T-bet positive Th1 cells in the -1993TT homozygotes were 2.2-fold higher than those in -1993CC homozygotes (p = 0.002). Our results suggest that the T-1993C polymorphism in the TBX21 promoter influences susceptibility to AIH-1 in a Chinese population.

MHC type II (MHC II) expression is tightly regulated in macrophages and potently induced by IFN-γ (type II IFN). In contrast, type I IFNs (IFN-Is), which are far more widely expressed, fail to induce MHC II expression, even though both classes of IFNs direct target gene expression through Stat1. The unexpected finding that IFN-Is effectively induce MHC II expression in Stat2−/− macrophages provided an opportunity to explore this conundrum. The ensuing studies revealed that deletion of Stat2, which uniquely transduces signals for IFN-Is, leads to a loss in the IFN-I-dependent induction of suppressor of cytokine signaling-1. Impairment in the expression of this important negative regulator led to a striking prolongation in IFN-I-dependent Stat1 activation, as well as enhanced expression of the target gene, IFN-regulatory factor-1. The prolonged activity of these two transcription factors synergized to drive the transcription of CIITA, the master regulator of MHC II expression, analogous to the pattern observed in IFN-γ-treated macrophages. Thus, IFN-I-dependent suppressor of cytokine signaling-1 expression plays an important role in distinguishing the biological response between type I and II IFNs in macrophages.

Long non-coding RNA (lncRNA) plays a role in gene transcription, protein expression and epigenetic regulation; and altered expression results in cancer development. Acute myeloid leukemia (AML) is rare in children; and thus, this study profiled lncRNA expression in bone marrow samples from pediatric AML patients. Arraystar Human LncRNA Array V3.0 was used to profile differentially expressed lncRNAs in three bone marrow samples obtained from each pediatric AML patient and normal controls. Quantitative polymerase chain reaction (qRT-PCR) was performed to confirm dysregulated lncRNA expressions in 22 AML bone marrow samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to construct the lncRNA-mRNA co-expression network. A total of 372 dysregulated lncRNAs (difference ≥10-fold) were found in pediatric AML patients compared to normal controls. Fifty-one mRNA levels were significantly upregulated, while 85 mRNA levels were significantly downregulated by >10-fold in pediatric AML, compared to normal controls. GO terms and KEGG pathway annotation data revealed that cell cycle pathway-related genes were significantly associated with pediatric AML. As confirmed by qRT-PCR, expression of 24 of 97 lncRNA was altered in pediatric AML compared to normal controls. In pediatric AML, ENST00000435695 was the most upregulated lncRNA, while ENST00000415964 was the most downregulated lncRNA. Data from this study revealed dysregulated lncRNAs and mRNAs in pediatric AML versus normal controls that could form gene pathways to regulate cell cycle progression and immunoresponse. Further studies are required to determine whether these lncRNAs could serve as novel therapeutic targets and bbdiagnostic biomarkers in pediatric AML.

To study the expression level and CpG island methylation status of miR-34b in leukemia cell lines and to research the effect of DNA methylation on the proliferation of leukemia cells regulated by miR-34b.Taqman real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was carried out to detect the relative expression of miR-34b in control group (bone marrow cells of 20 children without blood disease) and 8 leukemia cell lines (U937, HL-60, MV4-11, M2R, K562, Raji, CCRF, DAMI). Methylation-specific polymerase chain reaction (MSP) was carried out to detect the methylation differences of miR-34b in control group (Bone marrow cells of 23 children without blood disease), 8 leukemia cell lines. HL-60 and K562 were treated with methyltransferase inhibitor (5-aza-2-dC) for further detection of its methylation status and expression of miR-34b. Hsa-miR-34b mimics was transfected into K562 cell by liposome, the transfection efficiency was detected by flow cytometry. The cell proliferation of hsa-miR-34b transfected group in each stage was measured with CCK-8 assay, and then compared with non-transfected group and negative control group.The relative expression level of miR-34b in the group of children without blood disease and the group of leukemia cell lines were 5.22 ± 1.15, 0.03 ± 0.03. The results showed that, the group of leukemia cell lines was significantly different from the control group (t = 4.538, P0.01) . Eight leukemia cell lines showed methylation, the positive rate of the methyl was 100%. There was no methylation in the 23 cases of control group. After leukemia cell lines HL-60 and K562 were treated with 5-aza-2-dC, the methylated bands became obviously weakened, and the relative expression levels of miR-34b substantially increased 49.5 times and 18.8 times respectively. After hsa-miR-34b mimics was transfected into K562 cell by liposome, its transfection efficiency detected by flow cytometry was 61% and the cell proliferation was measured with CCK-8 assay from which it was found that the cell proliferation was significantly suppressed compared with the control group at 48 h (t = 9.303, P0.01), 72 h (t = 65.617, P0.01), 96 h (t = 36.878, P0.01) and 120 h (t = 18.748, P0.01) in hsa-miR-34b transfected group, with the inhibition rate of 12.2% (48 h), 45.7% (72 h), 32.5% (96 h) and 22.9% (120 h).The hypermethylation of promoter leads to decrease in the expression levels of miR-34b in leukemia cell lines, which attenuate mechanism of proliferative inhibition may be one of the reasons of occurrence or development of childhood leukemia.

In recent years, adenoviruses that selectively replicate in tumor cells have been developed. However, there is a tremendous need to improve their anticancer efficacy. We wish to investigate whether a strategy that combines the oncolytic effects of an adenoviral vector with simultaneous expression of soluble form of transforming growth factor-β type II receptor (sTGFβRII) offers a therapeutic advantage. We chose to target TGF-βs because they play a pivotal role in late-stage tumorigenesis by enhancing tumor invasion and metastasis. A sTGFβRII cDNA was cloned in conditionally replicating adenoviral vector rAd-sTRII and in a replication-deficient adenovirus Ad-sTRII. Infection of MDA-MB-231 breast cancer cells with rAd-sTRII or Ad-sTRII followed by Western blot analysis indicated the expression of diffused glycosylated forms of sTGFβRII that were also secreted into the extracellular medium. The secreted proteins were shown to bind with TGF-β and antagonize TGF-β–induced p38 mitogen-activated protein kinase activity. However, marked differences in the replication potential of rAd-sTRII and Ad-sTRII were observed in breast tumor cells. Infection of MDA-MB-231 cells with rAd-sTRII resulted in cytotoxicity and significant increase in the adenoviral titers that were comparable with a wild-type adenovirus dl309. However, Ad-sTRII was much less toxic to the tumor cells, and the viral titers of Ad-sTRII remained relatively unchanged. These results suggest that the infection of breast tumor cells with conditionally replicating adenoviral vector rAd-sTRII produced sTGFβRII that can abrogate TGF-β signaling while maintaining the replication potential of the virus, indicating that rAd-sTRII could be a potential anticancer agent. [Mol Cancer Ther 2006;5(2):367–73]

As most solid tumors are hypoxic, dendritic cells (DC) in solid tumors are also exposed to hypoxia. While many adaptation responses of tumor cells to hypoxia are known, it is yet to be determined how hypoxia affects the functions of DC. To explore the effects of hypoxia on the functions of DC, we compared the expression of surface markers, cytokines, chemokine receptors and matrix metalloproteinases (MMP) of human monocyte-derived DC (hmDC) differentiated under hypoxia to those differentiated under normoxia. Both groups of hmDC expressed similar levels of surface markers and cytokines. However, expression of MMP-9 and membrane type-1-MMP, as well as migrating activity, was significantly suppressed in hmDC differentiated under hypoxia compared with their normoxia counterparts. We also demonstrated that trichostatin A restored the production of MMP-9 in hmDC, under hypoxia. Collectively, our findings show that a hypoxic microenvironment suppresses the production of MMP in hmDC, most probably through the deacetylation of promoter regions of MMP, thus suppressing the migrating activity of hmDC. Our results suggest that the hypoxic microenvironment in solid tumor tissues may suppress the function of DC.

Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are characteristic of AML. Zinc finger protein 382 (ZNF382) has been suggested to be a tumor suppressor gene possibly regulated by promoter hypermethylation in various types of human cancer. However, ZNF382 expression and methylation status in pediatric AML is unknown. In the present study, ZNF382 transcription levels were evaluated by quantitative reverse-transcription PCR. Methylation status was investigated by methylation-specific (MSP) PCR and bisulfate genomic sequencing (BGS). The prognostic significance of ZNF382 expression and promoter methylation was assessed in 105 cases of pediatric AML. The array data suggested that the ZNF382 promoter was hypermethylated in the AML cases examined. MSP PCR and BGS analysis revealed that ZNF382 was hypermethylated in leukemia cell lines. Furthermore, treatment with 5-aza-2'-deoxycytidine (5-Aza) upregulated ZNF382 expression in the selected leukemia cell lines. The aberrant methylation of ZNF382 was observed in 10% (2/20) of the control samples compared with 26.7% (28/105) of the AML samples. ZNF382 expression was significantly decreased in the 105 AML patients compared with the controls. Patients with ZNF382 methylation showed lower ZNF382 transcript levels compared with patients exhibiting no methylation. There were no significant differences in clinical characteristics or cytogenetic analysis between the patients with or without ZNF382 methylation. ZNF382 methylation correlated with minimal residual disease (MRD). Kaplan-Meier survival analysis revealed similar survival times in the samples with ZNF382 methylation, and multivariate analysis revealed that ZNF382 methylation was not an independent prognostic factor in pediatric AML. The epigenetic inactivation of ZNF382 by promoter hypermethylation can be observed in AML cell lines and pediatric AML samples. Therefore, our study suggests that ZNF382 may be considered a putative tumor suppressor gene in pediatric AML. However, further studies focusing on the mechanisms responsible for ZNF382 downregulation in pediatric leukemia are required.

Background: Acute myeloid leukemia (AML) is the second most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature in various tumors, including AML. Metallothionein III (MT3) is a tumor suppresser reported to show promoter hypermethylated in various cancers. However, the expression and molecular function of MT3 in pediatric AML is unclear. Methods: Eleven human leukemia cell lines and 41 pediatric AML samples and 20 NBM/ITP (Norma bone marrow/ Idiopathic thrombocytopenic purpura) control samples were analyzed. Transcription levels of MT3 were evaluated by semi-quantitative and real-time PCR. MT3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BSG). The molecular mechanism of MT3 was investigated by apoptosis assays and PCR array analysis. Results: The MT3 promoter was hypermethylated in leukemia cell lines. More CpG’s methylated of MT3 was observed 39.0% pediatric AML samples compared to 10.0% NBM controls. Transcription of MT3 was also significantly decreased in AML samples compared to NBM/ITP controls (P< 0.001); patients with methylated MT3 exhibited lower levels of MT3 expression compared to those with unmethylated MT3 (P = 0.049). After transfection with MT3 lentivirus, proliferation was significantly inhibited in AML cells in a dose-dependent manner (P< 0.05). Annexin V assay showed that apoptosis was significantly upregulated MT3-overexpressing AML cells compared to controls. Real-time PCR array analysis revealed 34 dysregulated genes that may be implicated in MT3 overexpression and apoptosis in AML, including FOXO1. Conclusion: MT3 may be a putative tumor suppressor gene in pediatric AML. Epigenetic inactivation of MT3 via promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Overexpression of MT3 may inhibit proliferation and induce apoptosis in AML cells. FOXO1 was dysregulated in MT3-overexpressing cells, offering an insight into the mechanism of MT3-induced apoptosis. However, further research is required to determine the underlying molecular details.

Endometriosis is a complex disease that affects a large number of women worldwide and may cause pain and infertility. To systematically review published studies evaluating the relationship between menstrual cycle length and risk of endometriosis. We searched the Cochrane Library, PubMed, Web of Science, and EMBASE in databases in July 2014 using the keywords “case–control studies,” “epidemiologic determinants,” “risk factors,” “menstrual cycle,” “menstrual length,” “menstrual character,” and “endometriosis.” We included case–control studies published in English that investigated cases of surgically confirmed endometriosis and examined the relationship between endometriosis risk and menstrual cycle. Eleven articles that met the inclusion criteria included data of 3392 women with endometriosis and 5006 controls. Fixed-effects and random-effects models were used for the evaluation. For the association of risk of endometriosis and menstrual cycle length shorter than or equal to 27 days (SEQ27) or length longer than or equal to 29 days (LEQ29), the odds ratio was 1.22 (95% confidence interval [CI]: 1.05–1.43) and 0.68 (95% CI: 0.48–0.96), respectively. In conclusion, this meta-analysis suggests that menstrual cycle length SEQ27 increase the risk of endometriosis and cycle length LEQ29 decrease the risk.

Background The sexual dimorphism of hepatitis B virus (HBV) -related liver diseases is related with estrogen and its receptors. Recent reports indicate that abnormal expression of estrogen receptor alpha (ESR1) may be a hallmark for the progression of liver disease and HBV carriers presenting variant ESR1 have an extremely aggressive clinical course. Here we examine whether the ESR1 polymorphisms or its haplotypes are related to HBV-related acute liver failure (ALF) risk among chronic HBV carriers in a Chinese population. Methods A total of 1216 unrelated Han Chinese HBV carriers were recruited in this hospital-based case–control study, including 359 HBV surface antigen (HBsAg) carriers affected with ALF and 857 asymptomatic HBsAg carriers. Two ESR1 haplotype tagging polymorphisms, c.30 T > C (rs2077647) and c.453-397 T > C (rs2234693), were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results We observed a significantly increased susceptibility to HBV-ALF associated with the c.30 C allele (P = 8.65 × 10-4), c.453-397 C allele (5.37 × 10-4) and [c.30 C; c.453-397 C] haplotype (Dominant model, P =0.0004, odds ratio = 1.53, 95% CI 1.23 ~ 1.96) compared with the T alleles and [c.30 T; c.453-397 T] haplotype of c.30 T > C and c.453-397 T > C polymorphisms, respectively. Conclusions Our study suggests that [c.30 C; c.453-397 C] hapotype may be a risk factor for genetic susceptibility to HBV-related ALF in the Chinese population. It also emphasizes the importance of ESR1 in the pathophysiology of HBV-related ALF on the population level.

Cell transplantation has been well explored for cartilage regeneration. We recently showed that the entire articular surface of a synovial joint can regenerate by endogenous cell homing and without cell transplantation. However, the sources of endogenous cells that regenerate articular cartilage remain elusive. Here, we studied whether cytokines not only chemotactically recruit adipose stem cells (ASCs), mesenchymal stem cells (MSCs), and synovium stem cells (SSCs) but also induce chondrogenesis of the recruited cells. Recombinant human transforming growth factor-β3 (TGF-β3; 100 ng) and/or recombinant human stromal derived factor-1β (SDF-1β; 100 ng) was control released into an acellular collagen sponge cube with underlying ASCs, MSCs, or SSCs in monolayer culture. Although all cell types randomly migrated into the acellular collagen sponge cube, TGF-β3 and/or SDF-1β recruited significantly more cells than the cytokine-free control group. In 6 wk, TGF-β3 alone recruited substantial numbers of ASCs (558±65) and MSCs (302±52), whereas codelivery of TGF-β3 and SDF-1β was particularly chemotactic to SSCs (400±120). Proliferation of the recruited cells accounted for some, but far from all, of the observed cellularity. TGF-β3 and SDF-1β codelivery induced significantly higher aggrecan gene expression than the cytokine-free group for ASCs, MSCs, and SSCs. Type II collagen gene expression was also significantly higher for ASCs and SSCs by SDF-1 and TGF-β3 codelivery. Remarkably, the expression of aggrecan and type II collagen was detected among all cell types. Thus, homing of multiple stem/progenitor cell populations may potentially serve as an alternative or adjunctive approach to cell transplantation for cartilage regeneration.—Mendelson, A., Frank, E., Allred, C., Jones, E., Chen, M., Zhao, W., Mao, J. J. Chondrogenesis by chemotactic homing of synovium, bone marrow, and adipose stem cells in vitro.

Summary. Recent reports indicated that high levels of interleukin 10 (IL-10) contribute to the monocytes paralysis and poor clinical outcome in acute liver failure (ALF). Polymorphisms in the promoter region of IL-10 affect IL-10 production and confer susceptibility to inflammatory diseases. The aim of this study was to determine the possible association of the three polymorphisms (A-1082G, T-819C, A-592C) in the IL-10 gene promoter with the susceptibility to hepatitis B virus (HBV)-related ALF in a Chinese population. The IL-10 gene promoter polymorphisms were genotyped in 414 unrelated healthy blood donors, 367 asymptomatic HBV carriers and 345 HBV-related ALF patients. Functional analyses were conducted to verify the biological significances of the associated genetic variations. The allele frequencies of IL-10−592C and −819C were significantly higher in HBV-related ALF patients than in blood donors and asymptomatic HBV carriers. Logistic regression analysis and stratification analysis with adjustment for age and sex indicated that the polymorphisms of A-592C and T-819C were associated with susceptibility to HBV-related ALF (P = 6.9 × 10−7), and the -1082A-819C-592C haplotype in the IL-10 gene promoter were associated with an increased susceptibility to ALF in HBV carriers (dominant model, P = 0.0002, odds ratio = 1.60, 95% CI 1.25–2.07). Functional analyses showed that the A-592C polymorphism is a nuclear proteins binding site, and the disease susceptible −592C allele had a higher transcription activity compared with −592A allele. This study emphasizes the importance of IL-10 in the pathophysiology of HBV-related ALF on the population level.

B-cell acute lymphoblastic leukemia (B-ALL) accounts for the most cancer incidences in children. We present here that autophagy is downregulated in pediatric B-ALL, suggesting a possible link between autophagy failure and pediatric B-ALL leukemogenesis. With a pediatric t(1;19) B-ALL xenograft mouse model, we show here that activation of autophagy by preventive administration of rapamycin improved the survival of leukemia animals by partial restoration of hematopoietic stem/progenitor cells, whereas treatment of the animals with rapamycin caused leukemia bone marrow cell-cycle arrest. Activation of autophagy in vitro or in vivo by rapamycin or starvation downregulated oncogenic fusion protein E2A/Pbx1. Furthermore, E2A/Pbx1 was found to be colocalized with autophagy marker LC3 in autolysosomes and with ubiquitin in response to autophagy stimuli, whereas autophagy or ubiquitination inhibitor blocked these colocalizations. Together, our data suggest a collaborative action between autophagy and ubiquitination in the degradation of E2A/Pbx1, thereby revealing a novel strategy for targeted preventive or treatment therapy on the pediatric ALL.

Transforming growth factor (TGF) betas are multifunctional polypeptides that regulate several cellular functions, including cell growth and differentiation, extra cellular matrix production, motility and immunosuppression. The growth-inhibiting properties of TGFbeta have gained much attention into its role as a tumor suppressor. There is, however, now increasing evidence that TGFbeta switches roles, from tumor suppressor to tumor promoter, as the tumor progresses. Given the integral role of TGFbeta in the tumor progression, it follows that TGFbeta signaling offers an attractive target for cancer therapy. Several strategies including the use of antisense oligonucleotides for TGFbeta, TGFbeta antibodies, dominant negative TGFbeta receptor II, and small drug-molecules to inhibit TGFbeta receptor I kinase have shown great promise in the preclinical studies. These new findings, coupled with progressing clinical trials indicate that inhibition of TGFbeta signaling may, indeed, be a viable option to cancer therapy. This review summarizes the TGFbeta signaling, the dual role of TGFbeta--as a tumor suppressor and tumor promoter, and various strategies targeted against TGFbeta signaling for cancer therapy. The next few years promise to better our understanding of approaching cancer therapy with an eye to the inhibition of TGFbeta signaling.

We have recently demonstrated that granulocyte colony-stimulating factor (G-CSF) stimulated the production of epithelial-cell-derived-neutrophil attractant-78 (ENA-78) by neutrophils and that ENA-78 might promote the accumulation of neutrophils that had migrated from the intravascular space into inflammatory tissues. In this study, we examined whether other chemokines could be secreted by neutrophils that had accumulated after migrating from the intravascular space into the inflammatory tissues. We demonstrated that adhesion to laminin contained in the basement membrane and Matrigel, which is an artificial basement membrane model, induced macrophage inflammatory protein-1 beta (MIP-1 beta) in neutrophils and that MIP-1 beta secreted by neutrophils induced the chemotaxis of dendritic cells. These findings suggest that neutrophils transmigrating through the basement membrane are stimulated to secrete MIP-1 beta by the basement membrane, inducing the transmigration of dendritic cells from the intravascular space into inflammatory tissues. We propose that neutrophils intervene between innate immune response and specific immune response by secreting MIP-1 beta during the transmigration through the basement membrane.