Neutrophils Turn Plasma Proteins into Weapons against HIV-1

As a consequence of innate immune activation granulocytes and macrophages produce hypochlorite/hypochlorous acid (HOCl) via secretion of myeloperoxidase (MPO) to the outside of the cells, where HOCl immediately reacts with proteins. Most proteins that become altered by this system do not belong to the invading microorganism but to the host. While there is no doubt that the myeloperoxidase system is capable of directly inactivating HIV-1, we hypothesized that it may have an additional indirect mode of action. We show in this article that HOCl is able to chemically alter proteins and thus turn them into Idea-Ps (Idea-P = immune defence-altered protein), potent amyloid-like and SH-groups capturing antiviral weapons against HIV-1. HOCl-altered plasma proteins (Idea-PP) have the capacity to bind efficiently and with high affinity to the HIV-1 envelope protein gp120, and to its receptor CD4 as well as to the protein disulfide isomerase (PDI). Idea-PP was able to inhibit viral infection and replication in a cell culture system as shown by reduced number of infected cells and of syncytia, resulting in reduction of viral capsid protein p24 in the culture supernatant. The unmodified plasma protein fraction had no effect. HOCl-altered isolated proteins antithrombin III and human serum albumin, taken as representative examples of the whole pool of plasma proteins, were both able to exert the same activity of binding to gp120 and inhibition of viral proliferation. These data offer an opportunity to improve the understanding of the intricacies of host-pathogen interactions and allow the generation of the following hypothetical scheme: natural immune defense mechanisms generate by posttranslational modification of plasma proteins a potent virucidal weapon that immobilizes the virus as well as inhibits viral fusion and thus entry into the host cells. Furthermore simulation of this mechanism in vitro might provide an interesting new therapeutic approach against microorganisms

Influence of Genetic Variants in TPMT and COMT Associated with Cisplatin Induced Hearing Loss in Patients with Cancer:Two New Cohorts and a Meta-Analysis Reveal Significant Heterogeneity between Cohorts

Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested

A System Development Kit for Big Data Applications on FPGA-based Clusters: The EVEREST Approach

Modern big data workflows are characterized by computationally intensive kernels. The simulated results are often combined with knowledge extracted from AI models to ultimately support decision-making. These energy-hungry workflows are increasingly executed in data centers with energy-efficient hard-ware accelerators since FPG As are well-suited for this task due to their inherent parallelism. We present the H2020 project EVEREST, which has developed a system development kit (SDK) to simplify the creation of FPGA-accelerated kernels and manage the execution at runtime through a virtualization environment. This paper describes the main components of the EVEREST SDK and the benefits that can be achieved in our use cases

New Colloidal Lithographic Nanopatterns Fabricated by Combining Pre-Heating and Reactive Ion Etching

We report a low-cost and simple method for fabrication of nonspherical colloidal lithographic nanopatterns with a long-range order by preheating and oxygen reactive ion etching of monolayer and double-layer polystyrene spheres. This strategy allows excellent control of size and morphology of the colloidal particles and expands the applications of the colloidal patterns as templates for preparing ordered functional nanostructure arrays. For the first time, various unique nanostructures with long-range order, including network structures with tunable neck length and width, hexagonal-shaped, and rectangular-shaped arrays as well as size tunable nanohole arrays, were fabricated by this route. Promising potentials of such unique periodic nanostructures in various fields, such as photonic crystals, catalysts, templates for deposition, and masks for etching, are naturally expected

Clinical experience in T cell deficient patients

T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT) now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning

NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: A high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker

Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies

Multidimensional Atomic Force Microscopy: A Versatile Novel Technology for Nanopharmacology Research

Nanotechnology is giving us a glimpse into a nascent field of nanopharmacology that deals with pharmacological phenomena at molecular scale. This review presents our perspective on the use of scanning probe microscopy techniques with special emphasis to multidimensional atomic force microscopy (m-AFM) to explore this new field with a particular emphasis to define targets, design therapeutics, and track outcomes of molecular-scale pharmacological interactions. The approach will be to first discuss operating principles of m-AFM and provide representative examples of studies to understand human health and disease at the molecular level and then to address different strategies in defining target macromolecules, screening potential drug candidates, developing and characterizing of drug delivery systems, and monitoring target–drug interactions. Finally, we will discuss some future directions including AFM tip-based parallel sensors integrated with other high-throughput technologies which could be a powerful platform for drug discovery

Specific Loss of Histone H3 Lysine 9 Trimethylation and HP1γ/Cohesin Binding at D4Z4 Repeats Is Associated with Facioscapulohumeral Dystrophy (FSHD)

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy in which no mutation of pathogenic gene(s) has been identified. Instead, the disease is, in most cases, genetically linked to a contraction in the number of 3.3 kb D4Z4 repeats on chromosome 4q. How contraction of the 4qter D4Z4 repeats causes muscular dystrophy is not understood. In addition, a smaller group of FSHD cases are not associated with D4Z4 repeat contraction (termed “phenotypic” FSHD), and their etiology remains undefined. We carried out chromatin immunoprecipitation analysis using D4Z4–specific PCR primers to examine the D4Z4 chromatin structure in normal and patient cells as well as in small interfering RNA (siRNA)–treated cells. We found that SUV39H1–mediated H3K9 trimethylation at D4Z4 seen in normal cells is lost in FSHD. Furthermore, the loss of this histone modification occurs not only at the contracted 4q D4Z4 allele, but also at the genetically intact D4Z4 alleles on both chromosomes 4q and 10q, providing the first evidence that the genetic change (contraction) of one 4qD4Z4 allele spreads its effect to other genomic regions. Importantly, this epigenetic change was also observed in the phenotypic FSHD cases with no D4Z4 contraction, but not in other types of muscular dystrophies tested. We found that HP1γ and cohesin are co-recruited to D4Z4 in an H3K9me3–dependent and cell type–specific manner, which is disrupted in FSHD. The results indicate that cohesin plays an active role in HP1 recruitment and is involved in cell type–specific D4Z4 chromatin regulation. Taken together, we identified the loss of both histone H3K9 trimethylation and HP1γ/cohesin binding at D4Z4 to be a faithful marker for the FSHD phenotype. Based on these results, we propose a new model in which the epigenetic change initiated at 4q D4Z4 spreads its effect to other genomic regions, which compromises muscle-specific gene regulation leading to FSHD pathogenesis

ICF, An Immunodeficiency Syndrome: DNA Methyltransferase 3B Involvement, Chromosome Anomalies, and Gene Dysregulation

The immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) is the only disease known to result from a mutated DNA methyltransferase gene, namely, DNMT3B. Characteristic of this recessive disease are decreases in serum immunoglobulins despite the presence of B cells and, in the juxtacentromeric heterochromatin of chromosomes 1 and 16, chromatin decondensation, distinctive rearrangements, and satellite DNA hypomethylation. Although DNMT3B is involved in specific associations with histone deacetylases, HP1, other DNMTs, chromatin remodelling proteins, condensin, and other nuclear proteins, it is probably the partial loss of catalytic activity that is responsible for the disease. In microarray experiments and real-time RT-PCR assays, we observed significant differences in RNA levels from ICF vs. control lymphoblasts for pro- and anti-apoptotic genes (BCL2L10, CASP1, and PTPN13); nitrous oxide, carbon monoxide, NF-κB, and TNFa signalling pathway genes (PRKCH, GUCY1A3, GUCY1B3, MAPK13; HMOX1, and MAP4K4); and transcription control genes (NR2F2 and SMARCA2). This gene dysregulation could contribute to the immunodeficiency and other symptoms of ICF and might result from the limited losses of DNA methylation although ICF-related promoter hypomethylation was not observed for six of the above examined genes. We propose that hypomethylation of satellite 2at1qh and 16qh might provoke this dysregulation gene expression by trans effects from altered sequestration of transcription factors, changes in nuclear architecture, or expression of noncoding RNAs

Survival Trends and Long-Term Toxicity in Pediatric Patients with Osteosarcoma

Background. This study was conducted to investigate the clinical characteristics and treatment results of osteosarcoma in pediatric patients during the past 30 years. Trends in survival rates and long-term toxicity were analyzed. Procedure. 130 pediatric patients under the age of 20 years with primary localized or metastatic high-grade osteosarcoma were analyzed regarding demographic, treatment-related variables, long-term toxicity, and survival data. Results. Comparison of the different time periods of treatment showed that the 5-year OS improved from 58.6% for children diagnosed during 1979–1983 to 78.6% for those diagnosed during 2003–2008 (P=0.13). Interestingly, the basic treatment agents including cisplatin, doxorubicin, and methotrexate remained the same. Treatment reduction due to acute toxicity was less frequent in patients treated in the last era (7.1% versus 24.1% in patients treated in 1979–1983; P=0.04). Furthermore, late cardiac effects and secondary malignancies can become evident many years after treatment. Conclusion. We elucidate the prevalence of toxicity to therapy of patients with osteosarcoma over the past 30 years. The overall improvement in survival may in part be attributed to improved supportive care allowing regimens to be administered to best advantage with higher tolerance of chemotherapy and therefore less chemotherapy-related toxicity