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The accurate diagnosis and clinical management of traumatic brain injury (TBI) is currently limited by the lack of accessible molecular biomarkers that reflect the pathophysiology of this heterogeneous disease. To address this challenge, we developed a microchip diagnostic that can characterize TBI more comprehensively using the RNA found in brain-derived extracellular vesicles (EVs). Our approach measures a panel of EV miRNAs, processed with machine learning algorithms to capture the state of the injured and recovering brain. Our diagnostic combines surface marker-specific nanomagnetic isolation of brain-derived EVs, biomarker discovery using RNA sequencing, and machine learning processing of the EV miRNA cargo to minimally invasively measure the state of TBI. We achieved an accuracy of 99% identifying the signature of injured vs. sham control mice using an independent blinded test set (N = 77), where the injured group consists of heterogeneous populations (injury intensity, elapsed time since injury) to model the variability present in clinical samples. Moreover, we successfully predicted the intensity of the injury, the elapsed time since injury, and the presence of a prior injury using independent blinded test sets (N = 82). We demonstrated the translatability in a blinded test set by identifying TBI patients from healthy controls (AUC = 0.9, N = 60). This approach, which can detect signatures of injury that persist across a variety of injury types and individual responses to injury, more accurately reflects the heterogeneity of human TBI injury and recovery than conventional diagnostics, opening new opportunities to improve treatment of traumatic brain injuries. [ABSTRACT FROM AUTHOR]

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We review our experience and the literature in treating 4 patients with Wilms' tumor (WT) with intracardiac extension among 92 patients with this neoplasm. Cardiopulmonary bypass with circulatory arrest and profound hypothermia was used. There were 3 boys (3 years, 4 years 5 months, and 15 years) and 1 girl (6 years). The follow-up periods were 8 months, 3 years, 2 years 6 months, and 15 years, respectively. We had no surgical complications and conclude that the preoperative diagnosis is extremely important. These patients must be transferred to institutions where concomitant cardiac procedures can be performed. In treating patients with WT, Doppler ultrasound must be used preoperatively in all cases, not only those in which clinical and radiologic signs of intravascular involvement are found. We propose that preoperative chemotherapy should be used, as it shrinks the thrombus and causes desirable adherence of the thrombus to the venous wall, reducing the probability of thromboembolism during the surgical procedure. We also find this method safer than in our 1st case, where neither cardiac arrest nor hypothermia was used. Our results agree with the literature that intracardiac extension of WT does not worsen its prognosis when a rational surgical approach is used. [ABSTRACT FROM AUTHOR]

As influenza vaccination is now widely recommended, randomized clinical trials are no longer ethical in many populations. Therefore, observational studies on patients seeking medical care for acute respiratory illnesses (ARIs) are a popular option for estimating influenza vaccine effectiveness (VE). We developed a probability model for evaluating and comparing bias and precision of estimates of VE against symptomatic influenza from two commonly used case-control study designs: the test-negative design and the traditional case-control design. We show that when vaccination does not affect the probability of developing non-influenza ARI then VE estimates from test-negative design studies are unbiased even if vaccinees and non-vaccinees have different probabilities of seeking medical care against ARI, as long as the ratio of these probabilities is the same for illnesses resulting from influenza and non-influenza infections. Our numerical results suggest that in general, estimates from the test-negative design have smaller bias compared to estimates from the traditional case-control design as long as the probability of non-influenza ARI is similar among vaccinated and unvaccinated individuals. We did not find consistent differences between the standard errors of the estimates from the two study designs. [ABSTRACT FROM AUTHOR]

Context: All US states require proof of immunization for school entry. Exemptions are generally offered for medical, religious, or philosophical reasons, but the health consequences of claiming such exemptions are poorly documented.Objectives: To quantify the risk of contracting measles among individuals claiming religious and/or philosophical exemptions from immunization (exemptors) compared with vaccinated persons, and to examine the risk that exemptors pose to the nonexempt population.Design, Setting, and Participants: Population-based, retrospective cohort study of data from 1985 through 1992, collected by the Measles Surveillance System of the Centers for Disease Control and Prevention, as well as from annual state immunization program reports on prevalence of exemptors and vaccination coverage. The study group was restricted to individuals aged 5 to 19 years. To empirically determine and quantify community risk, a mathematical model was developed that examines the spread of measles through communities with varying proportions of exemptors and vaccinated children.Main Outcome Measures: Relative risk of contracting measles for exemptors vs vaccinated individuals based on cohort study data. Community risk of contracting measles derived from a mathematical model.Results: On average, exemptors were 35 times more likely to contract measles than were vaccinated persons (95% confidence interval, 34-37). Relative risk varied by age and year. Comparing the incidence among exemptors with that among vaccinated children and adolescents during the years 1985-1992 indicated that the 1989-1991 measles resurgence may have occurred 1 year earlier among exemptors. Mapping of exemptors by county in California indicated that exempt populations tended to be clustered in certain geographic regions. Depending on assumptions of the model about the degree of mixing between exemptors and nonexemptors, an increase or decrease in the number of exemptors would affect the incidence of measles in nonexempt populations. If the number of exemptors doubled, the incidence of measles infection in nonexempt individuals would increase by 5.5%, 18.6%, and 30.8%, respectively, for intergroup mixing ratios of 20%, 40%, and 60%.Conclusions: These data suggest the need for systematic review of vaccine-preventable incidents to examine the effect of exemptors, increased surveillance of the number of exemptors and cases among them, and research to determine the reasons why individuals claim exemptions. [ABSTRACT FROM AUTHOR]

Aims Evaluation of the diversity and antibacterial activity of bacteria cultivated from Mediterranean Axinella sponges and investigating the influence of culture conditions on antibacterial activity profiles of sponge bacteria. Methods and Results Based on 16 S rRNA gene sequence analysis, the 259 bacteria isolated from the three Mediterranean Axinella sponges A. cannabina, A. verrucosa and A. polypoides belonged to 41 genera from the four phyla Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria and included five potential newly cultured genera. In antagonistic streak assays, 87 isolates (34%) from 13 genera showed antibacterial activity towards at least one of the 10 environmental and laboratory test bacteria. The extracts and filtrates of 22 isolates grown under three different culture conditions were less often active as the isolates in the corresponding antagonistic streak assays. Changes in antibacterial activity profiles were isolate- and culture condition-specific. Conclusions Axinella sponges are a good source to cultivate phylogenetic diverse and hitherto novel bacteria, many of which with antibacterial activity. Analysis of induced antibacterial activities might enhance the role of sponge bacteria in efforts to isolate new antibiotics in the future. Significance and Impact of the Study This study was the first to investigate the diversity and antibacterial activity of bacteria isolated from A. cannabina and A. verrucosa. It highlights the potential importance of induced activity and the need for employing multiple culture conditions in antibacterial screening assays of sponge-associated bacteria. [ABSTRACT FROM AUTHOR]

Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN+/+ transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation. [ABSTRACT FROM AUTHOR]

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement. [ABSTRACT FROM AUTHOR]

Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies. [ABSTRACT FROM AUTHOR]

Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies. [ABSTRACT FROM AUTHOR]

Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies. [ABSTRACT FROM AUTHOR]

Resistance to cytotoxic drugs is thought to be a major cause of treatment failure in childhood neuroblastoma, and members of the ATP-binding cassette (ABC) transporter superfamily may contribute to this phenomenon by active efflux of chemotherapeutic agents from cancer cells. As a member of the C subfamily of ABC transporters, multidrug resistance-associated protein MRP4/ABCC4 has the ability to export a variety of endogenous and exogenous substances across the plasma membrane. In light of its capacity for chemotherapeutic drug efflux, MRP4 has been studied in the context of drug resistance in a number of cancer cell types. However, MRP4 also influences cancer cell biology independently of chemotherapeutic drug exposure, which highlights the potential importance of endogenous MRP4 substrates in cancer biology. Furthermore, MRP4 is a direct transcriptional target of Myc family oncoproteins and expression of this transporter is a powerful independent predictor of clinical outcome in neuroblastoma. Together these features suggest that inhibition of MRP4 may be an attractive therapeutic approach for neuroblastoma and other cancers that rely on MRP4. In this respect, existing options for MRP4 inhibition are relatively non-selective and thus development of more specific anti-MRP4 compounds should be a major focus of future work in this area [ABSTRACT FROM AUTHOR]

Background:In the INRG dataset, the hypothesis that any segmental chromosomal alteration might be of prognostic impact in neuroblastoma without MYCN amplification (MNA) was tested.Methods:The presence of any segmental chromosomal alteration (chromosome 1p deletion, 11q deletion and/or chromosome 17q gain) defined a segmental genomic profile. Only tumours with a confirmed unaltered status for all three chromosome arms were considered as having no segmental chromosomal alterations.Results:Among the 8800 patients in the INRG database, a genomic type could be attributed for 505 patients without MNA: 397 cases had a segmental genomic type, whereas 108 cases had an absence of any segmental alteration. A segmental genomic type was more frequent in patients >18 months and in stage 4 disease (P<0.0001). In univariate analysis, 11q deletion, 17q gain and a segmental genomic type were associated with a poorer event-free survival (EFS) (P<0.0001, P=0.0002 and P<0.0001, respectively). In multivariate analysis modelling EFS, the parameters age, stage and a segmental genomic type were retained in the model, whereas the individual genetic markers were not (P<0.0001 and RR=2.56; P=0.0002 and RR=1.8; P=0.01 and RR=1.7, respectively).Conclusion:A segmental genomic profile, rather than the single genetic markers, adds prognostic information to the clinical markers age and stage in neuroblastoma patients without MNA, underlining the importance of pangenomic studies. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common solid tumor in children less than 5 years of age. The early onset of neuroblastoma suggests that genes involved in fetal development and pregnancy may have a putative role in the etiology of neuroblastoma. The human leukocyte antigen subtype G ( HLA-G) molecule plays an important role in immune response regulation and appears to regulate immune tolerance during early pregnancy as well as tumor immunosurveillance. Elevated levels of soluble HLA-G (sHLA-G) have been detected in a number of malignancies including serum samples from neuroblastoma and have been reported to be predictive of tumor relapse in neuroblastoma. In light of previous investigations suggesting that single nucleotide polymorphisms in the HLA-G gene may impact on protein expression levels and isoform production, we examined the influence of HLA-G polymorphisms on the susceptibility and clinical outcome of neuroblastoma in 163 neuroblastoma patients and 404 healthy controls. The distribution of HLA-G polymorphisms, alleles, or allelic groups did not differ between children diagnosed with neuroblastoma and healthy controls. Our analyses did not detect an association between common HLA-G polymorphisms and clinical outcome in patients treated for neuroblastoma. [ABSTRACT FROM AUTHOR]

SUMMARYMathematical models of influenza pandemics are sensitive to changes in contact rates between individuals. We conducted population-based telephone surveys in four North Carolina counties to determine the number of social interactions between individuals during the 2007-2008 influenza season. Influenza activity was monitored through sentinel medical practices. Among 3845 adults, the number of social contacts varied with age, was lower on weekends than on weekdays, and further decreased during school holiday periods. Adults with influenza-like illnesses had fewer social contacts. Adults' contacts in the community setting increased during periods of peak influenza activity. Among 290 children, potential contacts (i.e. other people in the same location) were lowest among preschool-age children and decreased on weekends and during school holidays. In adjusted analyses, children's potential social contacts did not change during periods of peak influenza activity. These results should be useful for modelling influenza epidemics and pandemics and in planning mitigation and response strategies. [ABSTRACT FROM AUTHOR]

Mathematical models of influenza pandemics are sensitive to changes in contact rates between individuals. We conducted population-based telephone surveys in four North Carolina counties to determine the number of social interactions between individuals during the 2007–2008 influenza season. Influenza activity was monitored through sentinel medical practices. Among 3845 adults, the number of social contacts varied with age, was lower on weekends than on weekdays, and further decreased during school holiday periods. Adults with influenza-like illnesses had fewer social contacts. Adults' contacts in the community setting increased during periods of peak influenza activity. Among 290 children, potential contacts (i.e. other people in the same location) were lowest among preschool-age children and decreased on weekends and during school holidays. In adjusted analyses, children's potential social contacts did not change during periods of peak influenza activity. These results should be useful for modelling influenza epidemics and pandemics and in planning mitigation and response strategies. [ABSTRACT FROM PUBLISHER]

Aims: To gain an understanding of the environmental factors that affect the growth of the bacterium Sporosarcina pasteurii, the metabolism of the bacterium and the calcium carbonate precipitation induced by this bacterium to optimally implement the biological treatment process, microbial induced calcium carbonate precipitation (MICP), in situ. Methods and Results: Soil column and batch tests were used to assess the effect of likely subsurface environmental factors on the MICP treatment process. Microbial growth and mineral precipitation were evaluated in freshwater and seawater. Environmental conditions that may influence the ureolytic activity of the bacteria, such as ammonium concentration and oxygen availability, as well as the ureolytic activities of viable and lysed cells were assessed. Treatment formulation and injection rate, as well as soil particle characteristics are other factors that were evaluated for impact on uniform induction of cementation within the soils. Conclusions: The results of the study presented herein indicate that the biological treatment process is equally robust over a wide range of soil types, concentrations of ammonium chloride and salinities ranging from distilled water to full seawater; on the time scale of an hour, it is not diminished by the absence of oxygen or lysis of cells containing the urease enzyme. Significance and Impact of Study: This study advances the biological treatment process MICP towards field implementation by addressing key environmental hurdles faced with during the upscaling process. [ABSTRACT FROM AUTHOR]

The family of tripartite-motif (TRIM) proteins are involved in diverse cellular processes, but are often characterized by critical protein-protein interactions necessary for their function. TRIM16 is induced in different cancer types, when the cancer cell is forced to proceed down a differentiation pathway. We have identified TRIM16 as a DNA-binding protein with histone acetylase activity, which is required for the retinoic acid receptor β2 transcriptional response in retinoid-treated cancer cells. In this study, we show that overexpressed TRIM16 reduced neuroblastoma cell growth, enhanced retinoid-induced differentiation and reduced tumourigenicity in vivo. TRIM16 was only expressed in the differentiated ganglion cell component of primary human neuroblastoma tumour tissues. TRIM16 bound directly to cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells. TRIM16 reduced cell motility and this required downregulation of vimentin. Retinoid treatment and enforced overexpression caused TRIM16 to translocate to the nucleus, and bind to and downregulate nuclear E2F1, required for cell replication. This study, for the first time, demonstrates that TRIM16 acts as a tumour suppressor, affecting neuritic differentiation, cell migration and replication through interactions with cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells. [ABSTRACT FROM AUTHOR]

Myc oncoproteins and histone deacetylases (HDACs) modulate gene transcription and enhance cancer cell proliferation, and HDAC inhibitors are among the most promising new classes of anticancer drugs. Here, we show that N-Myc and c-Myc upregulated HDAC2 gene expression in neuroblastoma and pancreatic cancer cells, respectively, which contributed to N-Myc- and c-Myc-induced cell proliferation. Cyclin G2 (CCNG2) was commonly repressed by N-Myc and HDAC2 in neuroblastoma cells and by c-Myc and HDAC2 in pancreatic cancer cells, and could be reactivated by HDAC inhibitors. 5-bromo-2′-deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc- and HDAC2-induced cell proliferation. Dual crosslinking chromatin immunoprecipitation assay demonstrated that N-Myc acted as a transrepressor by recruiting the HDAC2 protein to Sp1-binding sites at the CCNG2 gene core promoter. Moreover, HDAC2 was upregulated, and CCNG2 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation of HDAC2 and suppression of CCNG2 in Myc-induced oncogenesis, and have significant implications for the application of HDAC inhibitors in the prevention and treatment of Myc-driven cancers. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 83–96 Background Changes in gastric histology associated with long-term maintenance therapy with lansoprazole for erosive oesophagitis have not been well described. Aim To evaluate the effect on gastric histology of long-term dose-titrated lansoprazole administered as maintenance therapy for up to 82 months in patients with erosive oesophagitis. Methods Sequential gastric biopsy specimens were obtained for evaluation of histological changes and Helicobacter pylori infection status. Results Active and chronic inflammation improved from baseline to final visit in a majority of patients receiving long-term therapy with lansoprazole, irrespective of baseline H. pylori infection status. Reductions in active inflammation in the gastric body and antrum were seen in 53% (17/32) and 67% (20/30) of H. pylori-positive patients, respectively, and in 88% (7/8) and 86% (12/14) of H. pylori-negative patients, respectively. Reductions in chronic inflammation in the gastric body and antrum were seen in 38% (12/32) and 47% (15/32) of H. pylori-positive patients, respectively, and in 58% (70/121) and 57% (68/120) of H. pylori-negative patients, respectively. No clinically meaningful increases in hyperplasia, dysplasia, neoplasia, intestinal metaplasia or atrophy were observed during the follow-up period. Conclusions Lansoprazole administered as maintenance therapy for up to 6 years in patients with erosive oesophagitis demonstrated gastric mucosal safety and was well tolerated. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing association of reduced folate carrier and methylenetetrahydrofolate reductase gene polymorphisms with clinical outcome in childhood acute lymphoblastic leukemia.

Background The clinical safety of long-term lansoprazole therapy for the maintenance of healed erosive oesophagitis has not been extensively studied in clinical trials. Aim To assess the long-term clinical safety of dose-titrated lansoprazole as maintenance therapy for up to 82 months in subjects with healed erosive oesophagitis. Methods Clinical safety was assessed by monitoring adverse events (AEs), laboratory data including serum gastrin levels, and endoscopy. Results Mean duration (± s.d.) of lansoprazole treatment during the titrated open-label period was 56 ± 24 months (range <1–82 months). Overall, 189 of 195 (97%) subjects experienced a total of 2825 treatment-emergent AEs. Most AEs occurred during the first year of treatment, were mild-to-moderate in severity and resolved while on treatment. Of 155 serious AEs (in 74 subjects), only two (colitis and rectal haemorrhage in one subject) were considered treatment-related. Sixty-nine of 195 subjects (35%) experienced 187 treatment-related AEs, with diarrhoea (10%), headache (8%) and abdominal pain (6%) being the most common. Gastrin levels ≥400 pg/mL were seen in 9% of subjects; hypergastrinemia was not associated with gastro-intestinal AEs or nodules/polyps. Conclusions Lansoprazole maintenance therapy for up to 6 years is safe and well tolerated in subjects with healed erosive oesophagitis. [ABSTRACT FROM AUTHOR]

Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (n=8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include MYCN status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies. [ABSTRACT FROM AUTHOR]

Medulloblastoma tumorigenesis caused by inactivating mutations in the PATCHED1 (PTCH1) gene is initiated by persistently activated Sonic Hedgehog (Shh) signaling in granule neuron precursors (GNPs) during the late stages of cerebellar development. Both normal cerebellar development and Shh-driven medulloblastoma tumorigenesis require N-Myc expression. However, the mechanisms by which N-Myc affects the stages of medulloblastoma initiation and progression are unknown. Here we used a mouse model of Ptch1 heterozygosity and medulloblastoma to show that increased N-Myc expression characterized the earliest selection of focal GNP hyperplasia destined for later tumor progression. Step-wise loss of Ptch1 expression, from tumor initiation to progression, led to incremental increases in N-Myc protein, rather than mRNA, expression. Increased N-Myc resulted in enhanced proliferation and death resistance of perinatal GNPs at tumor initiation. Sequential N-Myc protein phosphorylation at serine-62 and serine-62/threonine-58 characterized the early and late stages of medulloblastoma tumorigenesis, respectively. Shh pathway activation led to increased Myc protein stability and reduced expression of key regulatory factors. Taken together our data identify N-Myc protein stability as the result of loss of Ptch1, which distinguishes normal cerebellar development from medulloblastoma tumorigenesis.Oncogene (2009) 28, 1605–1615; doi:10.1038/onc.2009.3; published online 23 February 2009 [ABSTRACT FROM AUTHOR]

Increased retinoic acid receptor beta (RARbeta(2)) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARbeta(2) expression is a common feature of many human cancers, suggesting that RARbeta(2) may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARbeta(2) expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARbeta(2) protein alone was sufficient for the growth inhibitory effects of RARbeta(2) on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARbeta(2). The ectopic overexpression of the RARbeta(2) ABC domain was sufficient to induce ATP7A expression, whereas, RARbeta(2) siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor beta and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism. [ABSTRACT FROM AUTHOR]

A model material simulating the mechanical and surface properties of a real human skin was developed for use as a substrate in adhesion-to-skin evaluation. It is a protein–lipid composition possessing film-forming ability. The composition is based on gelatin plasticized by glycerol, polysaccharides and a mixture of lipids that mimick the skin's lipid structure and creates a hydrophobic surface. To enhance the material hydrolytic stability, the composition was cross-linked by formaldehyde, producing a water-swellable but insoluble matrix. The surface topography of a real skin was achieved by a silicone replica technique. Thin films with thickness of 100 ± 10 μm were cast. The effect of the components ratio and preparation technique on the film mechanical, surface and hydrolytic properties was studied. Based on the results obtained, a formulation having mechanical and surface properties comparable to that of a human skin was selected. The relevance of the model material was evaluated in lap-shear and 180°-peel adhesion tests and the results were compared to a finger or a forearm skin of ten healthy volunteers (in vivo tests). For validation purposes, commercial surgical tapes Micropore™ and Transpore™ and Mylar® polyester film were also used. The effects of substrate, adhesive, conditions of the joint preparation and the test employed on adhesion strength were studied. The results obtained show that the mechanical and surface properties of the model material are close to those of the human skin. [ABSTRACT FROM AUTHOR]

Background Chromogranin has been proposed as a marker for gastrin-dependent enterochromaffin-like cell proliferation. Aim To examine this question in three populations: acid hypersecretors with gastrinoma (Zollinger–Ellison), or without gastrinoma (non-Zollinger–Ellison), and also in pernicious anaemia with achlorhydria-caused hypergastrinaemia. Methods We measured serum chromogranin, gastrin, gastric secretion and counted and quantified hyperplasia of enterochromaffin-like cells in gastric biopsies from 38 Zollinger–Ellison and 13 non-Zollinger–Ellison patients being treated with lansoprazole, for 5 years (median) and again 2.5 years later. We also studied 12 patients with pernicious anaemia, half with gastric enterochromaffin-like cell carcinoids. Results Serum chromogranin was elevated in patients with gastrinoma, even without any enterochromaffin-like cell proliferation, but not in non-Zollinger–Ellison acid hypersecretors with normal gastrin ( P < 0.001). In the hypersecretors chromogranin correlated well with serum gastrin ( r = 0.82), but not with enterochromaffin-like cell proliferation. Moreover, chromogranin was normal or near normal (<75 ng/mL) despite very high serum gastrin in five of six patients with pernicious anaemia and enterochromaffin-like cell carcinoids. Conclusions Chromogranin is not a reliable marker for enterochromaffin-like cell activity or proliferation up to and including carcinoid; chromogranin originates in the gastrinoma and, like gastrin, is a marker for gastrinoma in acid hypersecretors. [ABSTRACT FROM AUTHOR]

We develop a Bayesian approach for estimating vaccine efficacy for susceptibility ( VE S ) and infectiousness ( VE I ) using outbreak size household data. Our method allows for heterogeneity in transmission probabilities due to factors that are related to individual' characteristics, such as age, in addition to vaccination status. It also allows for between-household heterogeneity in transmission probabilities due to random effects associated with households, such as genetic or environmental effects. Using age as a potential covariate causing heterogeneity in individual' transmission probabilities in households consisting of adults and children, we present the results of a simulation study designed to evaluate the performance of the proposed estimators of VE S and VE I . We found that estimates of VE I have larger bias and variance compared to those of VE S . We also use the approach to compare two vaccination designs: one vaccinating both adults and children, the other only children. Simulations reveal that the design that vaccinates both adults and children provides better estimates of V E S . There is no obvious difference between the two designs in the performance of the estimates of V E I . In regard to random effects between households and the scenarios considered, models that do not account for between-households heterogeneity produce fairly robust estimates even when household-level random effects are present. [ABSTRACT FROM AUTHOR]

Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16. [ABSTRACT FROM AUTHOR]

Objective: To examine the test-retest reliability of a protocol using an apparatus designed to standardise the standing heel rise test for the triceps surae muscle. Subjects: 40 healthy subjects volunteered to test short and medium term test-retest reliability (group SM, median age 24 years), and a convenience sample of 38 subjects with a history of unilateral deep vein thrombosis (DVT) volunteered to test long term test-retest reliability (group L median age 52 years). Design: Subjects carried out 23 heel rises per minute until either the pace or the height could no longer be maintained. Group SM subjects repeated the test 30 minutes later (short term), and again 48 hours later (medium term). Subjects in group L did the test on the unaffected leg, and repeated the test one week later (long term). Results: The median number of heel rises achieved per trial in group SM was 34 (range 16 to 120). The intraclass coefficient (ICC) was 0.93 (SEM 2.1) for both 30 minute and 48 hour test-retest reliability. In group L, the median number of heel rises was 27 (range 9 to 97), with ICC 0.88 and SEM 3.4. Conclusions: The apparatus is a simple and inexpensive standardised tool that reliably measures triceps surae fatigability in subjects with no current injury. Future research should assess its use in injured patients. [ABSTRACT FROM AUTHOR]

Background: The postthrombotic syndrome (PTS) occurs frequently after deep venous thrombosis (DVT) and is believed to worsen with upright posture and physical activity. However, the effects of exercise in patients with previous DVT have not been studied.Study Objectives: To determine whether previous DVT and PTS limit the ability to exercise, and whether exercise increases the severity of venous symptoms and signs.Design and Setting: A repeated-measures cohort study that was conducted at a university-affiliated teaching hospital, 1999-2000.Participants: Subjects with a first episode of unilateral DVT at least 1 year earlier were recruited from the Thrombosis Clinic (total, 41 subjects; with PTS, 19 subjects).Intervention: Treadmill exercise session.Measurements and Results: Venous symptoms, calf muscle fatigability, flexibility, and leg volume before and after treadmill exercise were measured and compared. Exercise did not worsen venous symptoms, despite a higher gain in affected leg volume in subjects with PTS vs subjects without PTS (mean difference: affected leg, 53 mL; unaffected leg, -15 mL; p = 0.018). Calf flexibility significantly improved after exercise in subjects with PTS (gastrocnemius: affected-unaffected, PTS vs no PTS + 4.5 degrees, p = 0.0029; soleus: affected-unaffected, PTS vs no PTS + 5.7 degrees, p = 0.0011).Conclusions: Exercise did not acutely exacerbate symptoms and, in subjects with PTS, resulted in improved flexibility in the affected leg. Our findings suggest that treadmill or similar exercise is unlikely to make symptoms of PTS worse, and may improve flexibility. Further study is indicated to determine whether a regular exercise-training program might have a role in the management of patients with PTS, since, to date, the treatment options for this condition are limited. [ABSTRACT FROM AUTHOR]

Resistance to the antifolate methotrexate (MTX) can cause treatment failure in childhood acute lymphoblastic leukemia (ALL). This may result from defective MTX accumulation due to alterations in the human reduced folate carrier (hRFC) gene. We have identified an hRFC gene point mutation in a transport-defective CCRF-CEM human T-ALL cell line resulting in a lysine to glutamic acid substitution at codon 45 (E45K), which has been identified in other antifolate-resistant sublines (JBC 273:30 189, 1998; JBC 275:30 855, 2000). To characterize the role of this mutation in MTX resistance, transfection experiments were performed using hRFC-null CCRF-CEM cells. E45K transfectants demonstrated an initial rate of MTX influx that was approximately 0.5-fold that of CCRF-CEM cells, despite marked protein overexpression. Cytotoxicity studies revealed partial reversal of MTX and raltitrexed resistance in E45K transfectants, while trimetrexate resistance was significantly increased. Kinetic analysis indicated only minor differences in MTX kinetics between wild-type and E45K hRFCs, however, K(i)s for folic acid and 5-formyltetrahydrofolate were markedly reduced for E45K hRFC. This was paralleled by increased folic acid transport and reduced synthesis of MTX polyglutamates. Collectively, the results demonstrate that expression of E45K hRFC leads to increased MTX resistance due to decreased membrane transport and, secondarily, from alterations in binding affinities and transport of folate substrates. However, despite these findings, we could find no evidence of this mutation in 121 childhood ALL samples, suggesting that it does not contribute to clinical MTX resistance in this disease. [ABSTRACT FROM AUTHOR]

We have previously reported a strong correlation between poor prognosis in childhood neuroblastoma (NB) patients and high-level expression of the transmembrane efflux pump, Multidrug Resistance-associated Protein (MRP1), in NB tumour tissue. In this study, we inhibited the endogenous expression ofMRP1 in 2 different NB tumour cell lines by stably transfecting anMRP1 antisense expression vector (MRP-AS). Compared with control cells, MRP-AS transfectant cells demonstrated a higher proportion of dead and morphologically apoptotic cells, spontaneous neuritogenesis, and, increased synaptophysin and neurofilament expression. Bcl-2 protein expression was markedly reduced in MRP-AS cells compared to controls. Conversely, we found that the same NB tumour cell line overexpressing the full-lengthMRP1 cDNA in sense orientation (MRP-S) demonstrated resistance to the neuritogenic effect of the differentiating agent, all-trans-retinoic acid. Taken together, the results suggest that the level of MRP1 expression in NB tumour cells may influence the capacity of NB cells for spontaneous regression in vivo through cell differentiation and death. [ABSTRACT FROM AUTHOR]

The molecular basis for the clinical presentation of broad-range drug resistance in childhood ALL is poorly understood. In this study, high level cross-resistance to the glucocorticoid dexamethasone was encountered in a childhood ALL cell line selected for resistance to methotrexate (CEM MTX-R3). Compared with wild-type (WT) CEM cells, MTX-R3 cells had significantly fewer glucocorticoid binding sites, as well as reduced glucocorticoid receptor protein and mRNA levels. DNA sequencing and restriction fragment-length polymorphism (RFLP) analysis showed that WT cells expressed both a wild-type and a mutant (GR753F) glucocorticoid receptor allele, while MTX-R3 cells expressed only the GR753F allele. Therefore, the cross-resistance of MTX-R3 cells to dexamethasone appeared due to loss of expression of the wild-type glucocorticoid receptor allele. In an effort to gain insight into the underlying basis for the development of cross-resistance to methotrexate and glucocorticoids, glucocorticoid receptor nuclear translocation experiments were carried out. Exposure of WT cells to either dexamethasone or the cytotoxic agents cytarabine and methotrexate caused translocation of the glucocorticoid receptor from the cytoplasm into the nucleus. These data indicate that exposure of childhood ALL cells to cytotoxic agents may result in ligand-independent glucocorticoid receptor activation which, in the context of the outgrowth of drug-resistant cells, could lead to the co-selection of glucocorticoid resistance. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori is said to cause atrophy of the gastric corpus and enterochromaffin-like cell proliferation in gastro-oesophageal reflux disease (GERD) patients treated long-term with a proton pump inhibitor. Aims: To determine the effect of H. pylori infection on gastritis, enterochromaffin-like cell density and hyperplasia, mucosal atrophy and serum gastrin in patients with gastric hypersecretion (basal acid output gt; 15 mmol/h) with either hypergastrinemia (Zollinger–Ellison syndrome) or normal gastrin (non-Zollinger–Ellison syndrome) before and during long-term treatment with lansoprazole. Methods: Lansoprazole was individually titrated to reduce basal acid output to < 5 mmol/h (< 1 mmol/h in post-surgical Zollinger–Ellison syndrome). Gastric corpus biopsies were obtained every 6 months before treatment and up to 8 years later. Results: H. pylori was present in corpus biopsies in ≈ 50%, causing active gastritis which resolved rapidly in 15 subjects after elimination of H. pylori. Patchy mild/moderate corpus atrophy was present at entry in two and at the end in four out of 60 patients, one being H. pylori-positive. Intestinal metaplasia (< 10%) was seen in six isolated biopsies (1% of total). H. pylori did not affect serum gastrin, enterochromaffin-like cell density or hyperplasia. Enterochromaffin-like cell density was twice as high in Zollinger–Ellison syndrome as in non-Zollinger–Ellison syndrome patients (241 vs. 126 cells/mm2, P < 0.001). Enterochromaffin-like cells remained normal in the non-Zollinger–Ellison syndrome hypersecretors regardless of H. pylori status. Conclusion: Corpus enterochromaffin-like cell increases were related to serum gastrin elevation, but neither H. pylori nor long-term treatment with lansoprazole alone or together had any effect on enterochromaffin-like cell density or hyperplasia. Corpus acute gastritis resulted from H. pylori infection, but did not... [ABSTRACT FROM AUTHOR]

A randomized, blinded, pilot study of influenza vaccine administered to children attending day care centers was conducted during the 1996-1997 winter. Vaccine efficacy in preventing serologically proven influenza virus infection was 0.45 (95% confidence limit [CL]: -0.02, 0.69) for influenza B and 0.31 (95% CL: -0.95, 0.73) for influenza A(H3N2). For both influenza A(H3N2) and B, children without preexisting hemagglutination inhibition (HI) antibody to these antigens had lower antibody responses to vaccine, were less likely to develop a serological response, and were more likely to develop serological evidence of influenza infection. Although there were no reductions in respiratory or febrile respiratory illnesses among all vaccinated children, there was a trend for reductions in such illnesses among vaccinated children with preexisting HI antibodies to influenza A(H3N2) and B. Therefore, immunologic priming in young children may be important for vaccine response and for protection against infection. Larger studies are needed in other influenza seasons to assess vaccine efficacy and clinical effectiveness. Copyright © 2000 The University of Chicago [ABSTRACT FROM AUTHOR]

Objective: Lansoprazole has undergone extensive clinical evaluation for the treatment of acid-peptic diseases. The aim of this study was to define the safety profile of lansoprazole and compare it to that of other therapeutic agents evaluated in the same controlled trials. Methods: The clinical safety profile of lansoprazole and comparative agents (placebo, ranitidine and omeprazole) was reviewed for 3281 patients who participated in short term (up to 8 weeks) and long term (up to 56 months) clinical trials conducted in the US. Adverse events, laboratory value changes and gastric biopsy changes that occurred during treatment were compared statistically for differences between treatments. Results: The incidence of adverse events and number of patients discontinuing treatment because of adverse events was similar for lansoprazole and comparative agents. Other than elevated serum gastrin levels, a known effect of proton pump inhibitors, no trends in laboratory changes were observed. Median values for gastrin levels remained within the normal range; about 2% of patients had gastrin levels >400 pg/ml at any time, while <1% had 2 or more gastrin values >500 pg/ml. Values returned to baseline levels after therapy was discontinued. No significant changes in gastric endocrine cell growth from baseline to final visit were observed, nor was there evidence of dysplasia or neoplasia. Conclusion: Lansoprazole is well tolerated for both short and long term treatment of acid-related disease. The tolerability of lansoprazole is comparable to that of ranitidine, omeprazole and placebo in the treatment of these diseases. [ABSTRACT FROM AUTHOR]

We have recently shown a close correlation between expression of the Multidrug Resistance-associated Protein (MRP) gene and the MYCN oncogene and provided evidence that high MRP expression is a powerful independent predictor of poor outcome in neuroblastoma (Norris et al., New Engl. J. Med., 334, 231 – 238, 1996). The effect of MYCN down-regulation on MRP expression and response to cytotoxic drugs was investigated in NBL-S neuroblastoma cells transfected wtih MYCN antisense RNA constructs. Concomitant with MYCN down-regulation, the level of MRP expression was decreased in the NBAS-4 and NBAS-5 antisense transfectants. These cells demonstrated significantly increased sensitivity to the high affinity MRP substrates vincristine, doxorubicin, sodium arsenate and potassium antimony tartrate, but not to the poor MRP substrates, taxol or cisplatin. Similarly, transfection of full-length MYCN cDNA into SH-EP neuroblastoma cells resulted in increased MRP expression and significantly increased resistance specifically to MRP substrates. The results provide evidence for the MYCN oncogene influencing cytotoxic drug response via regulation of MRP gene expression. Our data also provide a link between the malignant and chemoresistant phenotypes of this childhood malignancy. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy of two doses of lansoprazole with that of placebo in preventing recurrence of erosive esophagitis in a 12-month period.Design: Randomized, double-blind, parallel, placebo-controlled trial.Setting: 25 U.S. medical centers.Patients: 173 patients with documented healing of erosive esophagitis after 8 weeks of acid-suppressing therapy.Intervention: Lansoprazole, 15 mg or 30 mg, or placebo once daily for as long as 12 months.Measurements: Endoscopy and symptom evaluation after 1, 2, 3, 6, 9, and 12 months of treatment. Endoscopy was also done whenever symptoms suggested erosive changes.Results: Lansoprazole was significantly superior to placebo in maintaining healing and preventing recurrence of symptoms. By month 1, 45% of placebo recipients remained healed compared with more than 90% of patients in either lansoprazole group. By month 12, only 24% of placebo recipients remained healed compared with 79% of patients receiving 15 mg of lansoprazole and 90% of patients receiving 30 mg of lansoprazole. During the same period, 35% of placebo recipients remained asymptomatic compared with 72% of recipients of 15 mg of lansoprazole and 67% of recipients of 30 mg of lansoprazole. The 15-mg and 30-mg lansoprazole doses did not differ significantly in maintaining healing and controlling symptoms. Follow-up after recurrence of erosion indicated that during the 12 months, 35% of placebo recipients and 2% of lansoprazole recipients had three or more recurrences.Conclusion: Lansoprazole effectively maintains healing of erosive esophagitis. The 15-mg and 30-mg lansoprazole doses did not differ significantly for use as maintenance treatment. [ABSTRACT FROM AUTHOR]