Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ∼10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly ...expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of β-catenin at EMT gene promoters. We further show that cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit.
Display omitted
•ALK extracellular domain (ECD) cleavage occurs at Asn 654-Leu655•ECD cleavage mediates neuroblastoma (NB) cell migration•Cleavage inhibition leads to downregulated nuclear β-catenin and EMT gene signatures•ECD cleavage is caused by MMP-9 whose inhibition decreases NB cell migration
Huang et al. show that extracellular domain (ECD) cleavage of the ALK cell surface tyrosine kinase receptor mediates neuroblastoma cell migration through induction of an EMT phenotype. ECD cleavage is caused by MMP-9 whose inhibition leads to decreased cell migration.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neural crest cells are both highly migratory and significant to vertebrate organogenesis. However, the signals that regulate neural crest cell migration remain unclear. In this study, we test the ...function of differential screening-selected gene aberrant in neuroblastoma (DAN), a bone morphogenetic protein (BMP) antagonist we detected by analysis of the chick cranial mesoderm. Our analysis shows that, before neural crest cell exit from the hindbrain,
is expressed in the mesoderm, and then it becomes absent along cell migratory pathways. Cranial neural crest and metastatic melanoma cells avoid DAN protein stripes in vitro. Addition of DAN reduces the speed of migrating cells in vivo and in vitro, respectively. In vivo loss of function of DAN results in enhanced neural crest cell migration by increasing speed and directionality. Computer model simulations support the hypothesis that DAN restrains cell migration by regulating cell speed. Collectively, our results identify DAN as a novel factor that inhibits uncontrolled neural crest and metastatic melanoma invasion and promotes collective migration in a manner consistent with the inhibition of BMP signaling.
This pilot study explores the possibility of predicting post-concussion symptom recovery at one week post-injury using only objective diffusion tensor imaging (DTI) data inputs to a novel artificial ...intelligence (AI) system composed of Genetic Fuzzy Trees (GFT). Forty-three adolescents age 11 to 16 years with either mild traumatic brain injury or traumatic orthopedic injury were enrolled on presentation to the emergency department. Participants received a DTI scan three days post-injury, and their symptoms were assessed by the Post-Concussion Symptom Scale (PCSS) at 6 h and one week post-injury. The GFT system was trained using one-week total PCSS scores, 48 volumetric magnetic resonance imaging inputs, and 192 DTI inputs per participant over 225 training runs. Each training run contained a randomly selected 80% of the total sample followed by a 20% validation run. Over a different randomly selected sample distribution, GFT was also compared with six common classification methods. The cascading GFT structure controlled an effectively infinite solution space that classified participants as recovered or not recovered significantly better than chance. It demonstrated 100% and 62% classification accuracy in training and validation, respectively, better than any of the six comparison methods. Recovery sensitivity and specificity were 59% and 65% in the GFT validation set, respectively. These results provide initial evidence for the effectiveness of a GFT system to make clinical predictions of trauma symptom recovery using objective brain measures. Although clinical and research applications will necessitate additional optimization of the system, these results highlight the future promise of AI in acute care.
Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through ...anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of claudin-2.
IntroductionWomen of reproductive age (WRA) are a high-risk population for anaemia and micronutrient deficiencies. Evidence supports the role of periconceptional nutrition in the development of ...adverse pregnancy complications. However, in India, there are limited population-based data to guide evidence-based recommendations and priority setting. The objective of this study is to conduct a population-based biomarker survey of anaemia and vitamin B12 and folate status in WRA as part of a periconceptional surveillance programme in Southern India.MethodsWRA (15–40 years) who are not pregnant or lactating and reside within 50 km2 of our community research site in Southern India will be screened and invited to participate in the biomarker survey at our research facility at Arogyavaram Medical Centre. After informed consent/assent, structured interviews will be conducted by trained nurse enumerators to collect sociodemographic, dietary, anthropometry, health and reproductive history data. Venous blood samples will be collected at enrolment; whole blood will be analysed for haemoglobin. Plasma, serum and red blood cells (RBCs) will be processed and stored <−80°C until batch analysis. Vitamin B12 concentrations will be measured via chemiluminescence, and RBC and serum folate concentrations will be evaluated using the World Health Organisation (WHO)-recommended microbiological assay at our laboratory in Bangalore. A WHO surveillance system will also be established to determine the baseline prevalence of birth defects in this setting.Ethics and disseminationThis study has obtained clearance from the Health Ministry Screening Committee of the Indian Council of Medical Research. The study protocol was reviewed and approved by the Institutional Review Board at Cornell University and the Institutional Ethics Committees at Arogyavaram Medical Centre and St. John’s Research Institute. Findings from this biomarker survey will establish the burden of anaemia and micronutrient deficiencies in WRA and directly inform a randomised trial for anaemia and birth defects prevention in Southern India. The results of this study will be disseminated at international research conferences and as published articles in peer-reviewed journals.Trial registration numbersClinical trials registration number NCT04048330, NCT03853304 and Clinical Trials Registry of India (CTRI) registration number REF/2019/03/024479.
CONTEXT Early data on pandemic 2009 influenza A(H1N1) suggest pregnant women are at increased risk of hospitalization and death. OBJECTIVE To describe the severity of 2009 influenza A(H1N1) illness ...and the association with early antiviral treatment among pregnant women in the United States. DESIGN, SETTING, AND PATIENTS Surveillance of 2009 influenza A(H1N1) in pregnant women reported to the Centers for Disease Control and Prevention (CDC) with symptom onset from April through December 2009. MAIN OUTCOME MEASURES Severity of illness (hospitalizations, intensive care unit ICU admissions, and deaths) due to 2009 influenza A(H1N1) among pregnant women, stratified by timing of antiviral treatment and pregnancy trimester at symptom onset. RESULTS We received reports on 788 pregnant women in the United States with 2009 influenza A(H1N1) with symptom onset from April through August 2009. Among those, 30 died (5% of all reported 2009 influenza AH1N1 influenza deaths in this period). Among 509 hospitalized women, 115 (22.6%) were admitted to an ICU. Pregnant women with treatment more than 4 days after symptom onset were more likely to be admitted to an ICU (56.9% vs 9.4%; relative risk RR, 6.0; 95% confidence interval CI, 3.5-10.6) than those treated within 2 days after symptom onset. Only 1 death occurred in a patient who received treatment within 2 days of symptom onset. Updating these data with the CDC's continued surveillance of ICU admissions and deaths among pregnant women with symptom onset through December 31, 2009, identified an additional 165 women for a total of 280 women who were admitted to ICUs, 56 of whom died. Among the deaths, 4 occurred in the first trimester (7.1%), 15 in the second (26.8%), and 36 in the third (64.3%); CONCLUSIONS Pregnant women had a disproportionately high risk of mortality due to 2009 influenza A(H1N1). Among pregnant women with 2009 influenza A(H1N1) influenza reported to the CDC, early antiviral treatment appeared to be associated with fewer admissions to an ICU and fewer deaths.
When we were unable to identify an electronic data capture (EDC) package that supported our requirements for clinical research in resource-limited regions, we set out to build our own reusable EDC ...framework. We needed to capture data when offline, synchronize data on demand, and enforce strict eligibility requirements and complex longitudinal protocols. Based on previous experience, the geographical areas in which we conduct our research often have unreliable, slow internet access that would make web-based EDC platforms impractical. We were unwilling to fall back on paper-based data capture as we wanted other benefits of EDC. Therefore, we decided to build our own reusable software platform. In this paper, we describe our customizable EDC framework and highlight how we have used it in our ongoing surveillance programs, clinic-based cross-sectional studies, and randomized controlled trials (RCTs) in various settings in India and Ecuador.
This paper describes the creation of a mobile framework to support complex clinical research protocols in a variety of settings including clinical, surveillance, and RCTs.
We developed ConnEDCt, a mobile EDC framework for iOS devices and personal computers, using Claris FileMaker software for electronic data capture and data storage.
ConnEDCt was tested in the field in our clinical, surveillance, and clinical trial research contexts in India and Ecuador and continuously refined for ease of use and optimization, including specific user roles; simultaneous synchronization across multiple locations; complex randomization schemes and informed consent processes; and collecting diverse types of data (laboratory, growth measurements, sociodemographic, health history, dietary recall and feeding practices, environmental exposures, and biological specimen collection).
ConnEDCt is customizable, with regulatory-compliant security, data synchronization, and other useful features for data collection in a variety of settings and study designs. Furthermore, ConnEDCt is user friendly and lowers the risks for errors in data entry because of real time error checking and protocol enforcement.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We studied associations with winter habitat for seven species of birds, one species-group (eastern and western meadowlarks combined), and total sparrows at seven sites in the semidesert and plains ...grasslands of southeastern Arizona from 1999–2001, sampling with mist-nets and survey-transects. We measured structure and composition of vegetation, assessing vegetative differences among sites, and modeled associations between indices of avian abundance and six vegetative variables using generalized linear models. For all vegetative variables, there were significant differences among sites. Numbers of northern harriers (Circus cyaneus) were positively associated with total number of sparrows. Indices of abundance for individual species of birds were statistically correlated with various measures of structure and composition of vegetation. In particular, grasshopper (Ammodramus savannarum) and vesper (Pooecetes gramineus) sparrows were negatively associated with amount of bare ground; horned larks (Eremophila alpestris) were negatively associated with vertical grass density; Baird's sparrows (A. bairdii) were negatively associated with shrub density; meadowlarks (Sturnella magna and S. neglecta combined) were positively associated with native grass. Our results suggest that these species would benefit from management of habitat that affects the vegetative characteristics associated with their abundance.
Full text
Available for:
BFBNIB, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PDF
