136 research outputs found
Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.
Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed
Malignant melanoma in children and adolescents treated in pediatric oncology centers: an Australian and New Zealand Children's Oncology Group (ANZCHOG) Study
Objectives: Unlike adults, malignant melanoma in children and adolescents is rare. In adult melanoma, significant progress in understanding tumor biology and new treatments, including targeted therapies and immunotherapy have markedly improved overall survival. In sharp contrast, there is a paucity of data on the biology and clinical behavior of pediatric melanoma. We report a national case series of all pediatric and adolescent malignant melanoma presenting to ANZCHOG Childhood Cancer Centers in Australia and New Zealand. Methods: A retrospective, descriptive, multi-center study was undertaken to identify patients less than 18 years of age treated for cutaneous malignant melanoma over a twenty-year period (1994 to 2014). Data on clinical characteristics, histopathology, and extent of disease, treatment and follow-up are described. Results: A total of 37 cases of malignant melanoma were identified from all of the Australasian tertiary Childhood Cancer Centers. The median age was 10 years (range 1 month – 17 years). Clinically, the most common type of lesion was pigmented, occurring in sixteen (57%) patients, whilst amelanotic was seen in 7 patients (25%). In 11 (27.9%) the Breslow thickness was greater than 4mm. A total of 11 (29.7%) patients relapsed and 90% of these died of disease. Five-year event free survival (EFS) and overall survival were 63.2 (95% CI: 40.6 – 79.1) and 67.7% (95% CI: 45.1 – 82.6) respectively. Conclusion: Our data confirms that melanoma is a rare presentation of cancer to tertiary Australasian Childhood Cancer Centers with only 37 cases identified over two decades. Notably, melanoma managed in Childhood Cancer Centers is frequently at an advanced stage, with a high percentage of patients relapsing and the majority of these patients who relapsed died of disease. This study confirms previous clinical and prognostic information to support the early multidisciplinary management in Childhood Cancer Centers, in conjunction with expert adult melanoma centers, of this rare and challenging patient group.Anne L. Ryan, Charlotte Burns, Aditya K. Gupta, Ruvishani Samarasekera, David S. Ziegler, Maria L. Kirby, Frank Alvaro, Peter Downie, Stephen J. Laughton, Siobhan Cross, Timothy Hassall, Geoff B. McCowage, Jordan R. Hansford, Rishi S. Kotecha and Nicholas G. Gottard
photoproduction on the proton for photon energies from 0.725 to 2.875 GeV
Differential cross sections for the reaction have been
measured with the CEBAF Large Acceptance Spectrometer (CLAS) and a tagged
photon beam with energies from 0.725 to 2.875 GeV. Where available, the results
obtained here compare well with previously published results for the reaction.
Agreement with the SAID and MAID analyses is found below 1 GeV. The present set
of cross sections has been incorporated into the SAID database, and exploratory
fits have been made up to 2.7 GeV. Resonance couplings have been extracted and
compared to previous determinations. With the addition of these cross sections
to the world data set, significant changes have occurred in the high-energy
behavior of the SAID cross-section predictions and amplitudes.Comment: 18 pages, 10 figure
Differential cross sections and spin density matrix elements for the reaction gamma p -> p omega
High-statistics differential cross sections and spin density matrix elements
for the reaction gamma p -> p omega have been measured using the CLAS at
Jefferson Lab for center-of-mass (CM) energies from threshold up to 2.84 GeV.
Results are reported in 112 10-MeV wide CM energy bins, each subdivided into
cos(theta_CM) bins of width 0.1. These are the most precise and extensive omega
photoproduction measurements to date. A number of prominent structures are
clearly present in the data. Many of these have not previously been observed
due to limited statistics in earlier measurements
Splenic size after division of the short gastric vessels in Nissen fundoplication in children
Item does not contain fulltextPURPOSE: Nissen fundoplication is an effective treatment for gastro-esophageal reflux disease (GERD). Mobilization of the gastric fundus during fundoplication requires division of short gastric vessels of the spleen, which may cause splenic ischemia. The aim of this study was to determine if Nissen fundoplication results in hypotrophy of the spleen. METHODS: We performed pre-operative and post-operative ultrasound measurements of the spleen in children undergoing Nissen fundoplication. During operation, the surgeon estimated the compromised blood flow by assessment of the percentage of discoloration of the spleen. RESULTS: Twenty-four consecutive children were analyzed. Discoloration of the upper pole of the spleen was observed in 11 patients (48%) of a median estimated splenic surface of 20% (range 5-50%). The median ratio for pre-operative and post-operative length, width, and area of the spleen was 0.97, 1.03, and 0.96, respectively. The percentage of the estimated perfusion defect during surgery was not correlated with the ratios. In three patients, the area ratio was smaller than 0.8 (0.67-0.75), meaning that the area decreased with at least 20% after surgery. In none of these patients a discoloration was observed. CONCLUSION: Discoloration of the spleen after Nissen fundoplication is not associated with post-operative splenic atrophy.1 maart 201
Exclusive electroproduction on the proton at CLAS
The reaction has been measured, using the 5.754
GeV electron beam of Jefferson Lab and the CLAS detector. This represents the
largest ever set of data for this reaction in the valence region. Integrated
and differential cross sections are presented. The , and
dependences of the cross section are compared to theoretical calculations based
on -channel meson-exchange Regge theory on the one hand and on quark handbag
diagrams related to Generalized Parton Distributions (GPDs) on the other hand.
The Regge approach can describe at the 30% level most of the features
of the present data while the two GPD calculations that are presented in this
article which succesfully reproduce the high energy data strongly underestimate
the present data. The question is then raised whether this discrepancy
originates from an incomplete or inexact way of modelling the GPDs or the
associated hard scattering amplitude or whether the GPD formalism is simply
inapplicable in this region due to higher-twists contributions, incalculable at
present.Comment: 29 pages, 29 figure
The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial
\ua9 2023, The Author(s).BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m−2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485
Esomeprazole for the treatment of erosive esophagitis in children: an international, multicenter, randomized, parallel-group, double-blind (for dose) study
<p>Abstract</p> <p>Background</p> <p>Acid suppression with a proton pump inhibitor is standard treatment for gastroesophageal reflux disease and erosive esophagitis in adults and increasingly is becoming first-line therapy for children aged 1-17 years. We evaluated endoscopic healing of erosive esophagitis with esomeprazole in young children with gastroesophageal reflux disease and described esophageal histology.</p> <p>Methods</p> <p>Children aged 1-11 years with endoscopically or histologically confirmed gastroesophageal reflux disease were randomized to esomeprazole 5 or 10 mg daily (< 20 kg) or 10 or 20 mg daily (≥ 20 kg) for 8 weeks. Patients with erosive esophagitis underwent an endoscopy after 8 weeks to assess healing of erosions.</p> <p>Results</p> <p>Of 109 patients, 49% had erosive esophagitis and 51% had histologic evidence of reflux esophagitis without erosive esophagitis. Of the 45 patients who had erosive esophagitis and underwent follow-up endoscopy, 89% experienced erosion resolution. Dilation of intercellular space was reported in 24% of patients with histologic examination.</p> <p>Conclusions</p> <p>Esomeprazole (0.2-1.0 mg/kg) effectively heals macroscopic and microscopic erosive esophagitis in this pediatric population with gastroesophageal reflux disease. Dilation of intercellular space may be an important histologic marker of erosive esophagitis in children.</p> <p>Trial Registration</p> <p>D9614C00097; ClinicalTrials.gov identifier NCT00228527.</p
Environmental and Climatic Determinants of Molecular Diversity and Genetic Population Structure in a Coenagrionid Damselfly
Identifying environmental factors that structure intraspecific genetic diversity
is of interest for both habitat preservation and biodiversity conservation.
Recent advances in statistical and geographical genetics make it possible to
investigate how environmental factors affect geographic organisation and
population structure of molecular genetic diversity within species. Here we
present a study on a common and wide ranging insect, the blue tailed damselfly
Ischnuraelegans, which has been the target of many
ecological and evolutionary studies. We addressed the following questions: (i)
Is the population structure affected by longitudinal or latitudinal gradients?;
(ii) Do geographic boundaries limit gene flow?; (iii) Does geographic distance
affect connectivity and is there a signature of past bottlenecks?; (iv) Is there
evidence of a recent range expansion and (vi) what is the effect of geography
and climatic factors on population structure? We found low to moderate genetic
sub-structuring between populations (mean
FST = 0.06,
Dest = 0.12), and an effect of longitude, but
not latitude, on genetic diversity. No significant effects of geographic
boundaries (e.g. water bodies) were found. FST-and
Dest-values increased with geographic distance; however, there was no
evidence for recent bottlenecks. Finally, we did not detect any molecular
signatures of range expansions or an effect of geographic suitability, although
local precipitation had a strong effect on genetic differentiation. The
population structure of this small insect has probably been shaped by ecological
factors that are correlated with longitudinal gradients, geographic distances,
and local precipitation. The relatively weak global population structure and
high degree of genetic variation within populations suggest that I.
elegans has high dispersal ability, which is consistent with this
species being an effective and early coloniser of new habitats
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