87 research outputs found
Local and systemic effect of transfection-reagent formulated DNA vectors on equine melanoma
Background Equine melanoma has a high incidence in grey horses. Xenogenic DNA
vaccination may represent a promising therapeutic approach against equine
melanoma as it successfully induced an immunological response in other species
suffering from melanoma and in healthy horses. In a clinical study, twenty-
seven, grey, melanoma-bearing, horses were assigned to three groups (n = 9)
and vaccinated on days 1, 22, and 78 with DNA vectors encoding for equine (eq)
IL-12 and IL-18 alone or in combination with either human glycoprotein (hgp)
100 or human tyrosinase (htyr). Horses were vaccinated intramuscularly, and
one selected melanoma was locally treated by intradermal peritumoral
injection. Prior to each injection and on day 120, the sizes of up to nine
melanoma lesions per horse were measured by caliper and ultrasound. Specific
serum antibodies against hgp100 and htyr were measured using cell based flow-
cytometric assays. An Analysis of Variance (ANOVA) for repeated measurements
was performed to identify statistically significant influences on the relative
tumor volume. For post-hoc testing a Tukey-Kramer Multiple-Comparison Test was
performed to compare the relative volumes on the different examination days.
An ANOVA for repeated measurements was performed to analyse changes in body
temperature over time. A one-way ANOVA was used to evaluate differences in
body temperature between the groups. A p–value < 0.05 was considered
significant for all statistical tests applied. Results In all groups, the
relative tumor volume decreased significantly to 79.1 ± 26.91% by day 120 (p <
0.0001, Tukey-Kramer Multiple-Comparison Test). Affiliation to treatment
group, local treatment and examination modality had no significant influence
on the results (ANOVA for repeated measurements). Neither a cellular nor a
humoral immune response directed against htyr or hgp100 was detected. Horses
had an increased body temperature on the day after vaccination. Conclusions
This is the first clinical report on a systemic effect against equine melanoma
following treatment with DNA vectors encoding eqIL12 and eqIL18 and formulated
with a transfection reagent. Addition of DNA vectors encoding hgp100
respectively htyr did not potentiate this effect
Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries
Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.
Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway
Elimination Therapy for the Endemic Malarias
Most malaria diagnosed outside endemic zones occurs in patients experiencing the consequences of what was likely a single infectious bite by an anopheline mosquito. A single species of parasite is nearly always involved and expert opinion on malaria chemotherapy uniformly prescribes species- and stage-specific treatments. However the vast majority of people experiencing malaria, those resident in endemic zones, do so repeatedly and very often with the involvement of two or more species and stages of parasite. Silent forms of these infections—asymptomatic and beyond the reach of diagnostics—may accumulate to form substantial and unchallenged reservoirs of infection. In such settings treating only the species and stage of malaria revealed by diagnosis and not others may not be sensible or appropriate. Developing therapeutic strategies that address all species and stages independently of diagnostic evidence may substantially improve the effectiveness of the control and elimination of endemic malaria
Chlorination disinfection by-products in drinking water and congenital anomalies: review and meta-analyses
Pan-cancer analysis of whole genomes
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe
Influences of Sense of Place on Farming Households’ Relocation Willingness in Areas Threatened by Geological Disasters: Evidence from China
Magnesium mobility in soils as a challenge for soil and plant analysis, magnesium fertilization and root uptake under adverse growth conditions
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