Metabolic syndrome and type 2 diabetes are associated with increased risk of breast cancer development and progression. Methylglyoxal (MG), a glycolysis by-product, is generated through a ...non-enzymatic reaction from triose-phosphate intermediates. This dicarbonyl compound is highly reactive and contributes to the accumulation of advanced glycation end products. In this study, we analyzed the accumulation of Arg-pyrimidine, a MG-arginine adduct, in human breast adenocarcinoma and we observed a consistent increase of Arg-pyrimidine in cancer cells when compared with the non-tumoral counterpart. Further immunohistochemical comparative analysis of breast cancer subtypes revealed that triple negative lesions exhibited low accumulation of Arg-pyrimidine compared with other subtypes. Interestingly, the activity of glyoxalase 1 (Glo-1), an enzyme that detoxifies MG, was significantly higher in triple negative than in other subtype lesions, suggesting that these aggressive tumors are able to develop an efficient response against dicarbonyl stress. Using breast cancer cell lines, we substantiated these clinical observations by showing that, in contrast to triple positive, triple negative cells induced Glo-1 expression and activity in response to MG treatment. This is the first report that Arg-pyrimidine adduct accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus predominantly affecting immunocompromised ...individuals. Nowadays, HIV, hematological malignancies and iatrogenic immune suppression account for most PML cases. For unknown reasons, spinal cord is classically protected from PML lesions. Here, we report the course of a patient harboring spinal cord lesions in the context of PML with immune reconstitution inflammatory syndrome and review the eight other cases reported in the literature so far. Then, we discuss the evolving spectrum of PML over recent years, potentially making its diagnosis more challenging.
Synovial tissue research has become widely developed in several rheumatology centres, however, large discrepancies exist in the way synovial tissue is handled and, more specifically, how data ...pertaining to biopsy procedure, quality check and experimental results are reported in the literature. This heterogeneity hampers the progress of research in this rapidly expanding field. In that context, under the umbrella of European Alliance of Associations for Rheumatology, we aimed at proposing points to consider (PtC) for minimal reporting requirements in synovial tissue research.
Twenty-five members from 10 countries across Europe and USA met virtually to define the key areas needing evaluation and formulating the research questions to inform a systematic literature review (SLR). The results were presented during a second virtual meeting where PtC were formulated and agreed.
Study design, biopsy procedures, tissue handling, tissue quality control and tissue outcomes (imaging, DNA/RNA analysis and disaggregation) were identified as important aspects for the quality of synovial tissue research. The SLR interrogated four databases, retrieved 7654 abstracts and included 26 manuscripts. Three OPs and nine PtC were formulated covering the following areas: description of biopsy procedure, overarching clinical design, patient characteristics, tissue handling and processing, quality control, histopathology, transcriptomic analyses and single-cell technologies.
These PtC provide guidance on how research involving synovial tissue should be reported to ensure a better evaluation of results by readers, reviewers and the broader scientific community. We anticipate that these PtC will enable the field to progress in a robust and transparent manner over the coming years.
Hans Joachim Scherer (1906–1946) was a German pathologist who fled Germany to Belgium to work on glioma genesis, growth and progression. Despite being seldom cited, and due to the contributions ...discussed in this article, Hans Joachim Scherer, can be considered a founding father of contemporary neuropathology and glioma research. We discuss Scherer’s achievements in glioma classification, glomerular structures of glioma, primary and secondary glioblastoma, glioma growth patterns, non-resectability of glioma, pseudopalisadic necrosis and the late occurrence of symptoms in glioma.
Oligo-astrocytoma in LZTR1-related Noonan syndrome Jacquinet, Adeline; Bonnard, Adeline; Capri, Yline ...
European journal of medical genetics,
01/2020, Letnik:
63, Številka:
1
Journal Article, Web Resource
Recenzirano
Odprti dostop
Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan ...syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan syndrome and a previous treatment with growth hormone.
Asporin is extracellular matrix protein that has been associated with bone and joint diseases. Using innovative proteomic analysis we have previously found asporin as overexpressed in pancreas and ...breast cancer. In the current work we explore for the first time the functional significance of asporin expression in cancer. We show in 150 cases of breast carcinoma that asporin is a consistent feature of the tumor, whose high levels positively correlate with the good patient outcome. On the molecular level we demonstrate that only tumor‐associated fibroblasts are able to secrete asporin after being reprogrammed by the cancer cells. We found that TGF‐β‐1 alone is able to induce asporin expression and in turn asporin can bind TGF‐β‐1 to inhibit its action on TGF‐β receptors. The main interaction between the two proteins occurs via asporin 159‐205 amino acid region. Synthetic peptide corresponding to this key asporin segment is able to inhibit TGF‐β‐1 induction of SMAD2 phosphorylation in breast cancer cells. Using a TGF‐β‐1‐based model of epithelial to mesenchymal transition (EMT) in A549 cells, we further show that asporin peptide is able to inhibit TGF‐β‐1‐induced EMT.
Our work identifies asporin as a natural inhibitor of TGF‐β‐1 activity in cancer, offering a novel possibility of targeting TGF‐β‐1‐driven tumor progression.
Grant Funding Source: University of Liege
Functional targeted therapy has unfortunately failed to improve the outcome of glioblastoma patients. Success stories evidenced by the use of antibody–drug conjugates in other tumor types are ...encouraging, but targets specific to glioblastoma and accessible through the bloodstream remain scarce. In the current work, we have identified and characterized novel and accessible proteins using an innovative proteomic approach on six human glioblastomas; the corresponding data have been deposited in the PRIDE database identifier PXD001398. Among several clusters of uniquely expressed proteins, we highlight collagen-VI-alpha-1 (COL6A1) as a highly expressed tumor biomarker with low levels in most normal tissues. Immunohistochemical analysis of glioma samples from 61 patients demonstrated that COL6A1 is a significant and consistent feature of high-grade glioma. Deposits of COL6A1 were evidenced in the perivascular regions of the tumor-associated vasculature and in glioma cells found in pseudopalisade structures. Retrospective analysis of public gene-expression data sets from over 300 glioma patients demonstrated a significant correlation of poor patient outcome and high COL6A1 expression. In a proof-of-concept study, we use chicken chorioallantoic membrane in vivo model to show that COL6A1 is a reachable target for IV-injected antibodies. The present data warrant further development of human COL6A1 antibodies for assessing the quantitative biodistribution in the preclinical tumor models.
To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data ...from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53. Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo. In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.
Brain abscess is the most common focal infectious neurological injury. Until the nineteenth century this condition was fatal, however the development of neuroimaging for early diagnosis, neurosurgery ...and antibiotic therapy in the twentieth century has led to new therapeutic strategies decreasing mortality from 50 % in the 1970s to less than 10 % nowadays. In this context we report a case of brain abscess with a dental origin.
A immunocompetent man without any addiction presented to the emergency department with dysarthria and frontal headache at home. The clinical examination was normal. Further investigations revealed a polymicrobial brain abscess as a consequence of an ear, nose or throat (ENT) infection with locoregional extension with a dental starting point involving
and
. In spite of a rapid diagnosis and a neurosurgical management associated with an optimal treatment by a dual therapy made of ceftriaxone and metronidazole the patient unfortunately died.
This case report shows that despite a low incidence and a good prognosis following the diagnosis, brain abscesses can lead to patient's death. Thereby, when the patient's condition and urgency allow, a thorough dental examination of patients with neurological signs following the recommendations would improve the diagnosis made by the clinician. The use of microbiological documentation, the respect of pre-analytical conditions, the interaction between the laboratory and the clinicians are indispensable for an optimal management of these pathologies.
Metabolic disorders influence breast cancer development and progression.
Methylglyoxal (MGX), is a highly reactive glycolytic byproduct able to inflict carbonyl stress to proteins, lipids and DNA. ...The possible role of MGX in breast cancer development has not been yet extensively explored. We analyzed the accumulation of Arg‐pyrimidine adducts, in a series of more than 100 human breast adenocarcinoma and we observed a consistent increased of MGX adducts in cancer cells compared to the non‐tumoral counterpart. Most triple negative lesions examined exhibited low accumulation of Arg‐pyrimidine residues compared other subtypes. Intriguingly, the level of expression of glyoxalase 1 (Glo‐1), an enzyme that detoxifies MGX, was similar in both triple negative and other subtype lesions, suggesting a potential difference in the Glo‐1 activity. This hypothesis is supported by our preliminary results on breast cancer cell lines, showing that triple negative cells are more efficient to respond to treatment with MGX by increasing the activity of Glo‐1. Our study represent the first observation that Arg‐pyrimidine adducts accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes. Our preliminary data suggest that methylglyoxal production and detoxification could be a molecular link between metabolic diseases and breast cancer.
Grant Funding Source: This study is supported by Founds for National Research (FNRS), Belgium
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