Notes

How to end disproportionation of a hydrochloride sea salt of a quite weakly standard compound in a non-clinical headgear formula.
As JAK2 is essential for hematopoietic cytokine signaling, we also tested a JAK1-selective inhibitor and observed therapeutic benefit without apparent toxicity, though it did not improve survival when combined with anti-IFN-g. We conclude that continuous blockade of IFN-g signaling is necessary for optimal control of HLH and that JAK2 inhibition may be toxic in this disorder.Gene therapy as a potential cure for sickle cell disease (SCD) has long been pursued given that this hemoglobin disorder results from a single point mutation. Advances in genomic sequencing, increased understanding of hemoglobin regulation and discoveries of molecular tools for genome modification of hematopoietic stem cells have made gene therapy for SCD possible. Gene addition strategies using gene transfer vectors have been optimized over the last few decades to enable expression of normal or anti-sickling globins as strategies to ameliorate SCD. Many hurdles had to be addressed prior to clinical translation including collection of sufficient stem cells for gene-modification, increasing expression of transferred genes to a therapeutic level and conditioning patients in a safe manner that enabled adequate engraftment of gene-modified cells. The discovery of genome editors that make precise modifications has further advanced the safety and efficacy of gene therapy and a rapid movement to clinical trial has undoubtedly been supported by lessons learned from optimizing gene addition strategies. Current gene therapies being tested in clinical trial require significant infrastructure and expertise given the needs to harvest cells from and administer chemotherapy to patients who often have significant organ dysfunction and that gene-modification takes place ex vivo in specialized facilities. For these therapies to realize their full potential they would need to be portable, safe and efficient making an in-vivo based approach attractive. Additionally, adequate resources for SCD screening and access to standardized care are critically important for gene therapy to be a viable treatment option for SCD.The multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Of note, SARS-CoV Nsp3 contains a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. We show herein that the SARS-CoV-2 Nsp3 protein also contains a SUD domain that interacts with G4s. Indeed, interactions between SUD proteins and both DNA and RNA G4s were evidenced by G4 pull-down, Surface Plasmon Resonance and Homogenous Time Resolved Fluorescence. These interactions can be disrupted by mutations that prevent oligonucleotides from folding into G4 structures and, interestingly, by molecules known as specific ligands of these G4s. Structural models for these interactions are proposed and reveal significant differences with the crystallographic and modeled 3D structures of the SARS-CoV SUD-NM/G4 interaction. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARS-CoV-2 replication and the use of inhibitors of these interactions as potential antiviral compounds.The collection of microorganisms living in the mammalian gastrointestinal tract, termed the gut microbiota, has been shown to have profound impacts on host health and increasingly is regarded as a viable therapeutic target. Clinical studies of fecal microbiota transplantation (FMT) have demonstrated potential efficacy of microbiota-based therapies for diseases including Clostridioides difficile infections, inflammatory bowel disease, graft-versus-host disease and cancer. However, the lack of understanding of the active ingredients and potential risks of such therapies pose challenges for clinical application. Meanwhile, efforts are being made to identify effector microbes directly associated with a given phenotype, to establish causality and to devise well-characterized microbial therapeutics for clinical use. Strategies based on defined microbial components will likely enhance the potential of microbiota-targeted therapies.Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma, the leading childhood cancer in sub-Saharan Africa. Burkitt cells retain aspects of germinal center B-cell physiology with MYC-driven B-cell hyperproliferation, yet little is presently known about their iron metabolism. LDC7559 in vivo CRISPR/Cas9 analysis highlighted the little studied ferrireductase CYB561A3 as critical for Burkitt proliferation, but not for that of closely related EBV-transformed lymphoblastoid cells or nearly all other Cancer Dependency Map cell lines. Burkitt CYB561A3 knockout induced profound iron starvation, despite ferritinophagy and plasma membrane transferrin upregulation. Elevated concentrations of ascorbic acid, a key CYB561 family electron donor or the labile iron source ferrous citrate rescued Burkitt CYB561A3 deficiency. CYB561A3 knockout caused catastrophic lysosomal and mitochondrial damage and impaired mitochondrial respiration. By contrast, lymphoblastoid B-cells with the transforming EBV latency III program were instead dependent on the STEAP3 ferrireductase. These results highlight CYB561A3 it as an attractive therapeutic Burkitt lymphoma target.
RET gene fusions are oncogenic drivers in nonsmall cell lung cancer and nonmedullary thyroid cancer. Selpercatinib (RETEVMO), a targeted inhibitor of RET, was approved by the US Food and Drug Administration for the treatment of RET fusion-positive nonsmall cell lung cancer and nonmedullary thyroid cancer emphasizing the need for rapid and accurate diagnosis of RET fusions. Fluorescence in situ hybridization (FISH) has been used to detect gene rearrangements, but its performance detecting RET rearrangements is understudied.

To validate and describe the performance of Abbott Molecular RET break-apart FISH probes for detecting RET rearrangements.

A training set with RET fusion-positive (13) and RET fusion-negative nonsmall cell lung cancer and nonmedullary thyroid cancer samples (12) was used to establish criteria for FISH scoring. The scoring criteria was then applied to a larger validation set of samples (96).

A cutoff of 19% or more positive nuclei by FISH was established in the training set and determined by the mean ±3 SD. The validation set was tested using Abbott Molecular RET break-apart FISH compared with sequencing. With this cutoff, a sensitivity of 86% (12 of 14) and specificity of 99% (81 of 82) was achieved. Bootstrapping showed sensitivity could be optimized by using a greater than 13% cutoff with indeterminate samples of 13% to 18% abnormal nuclei requiring confirmation by an orthogonal method. Using this 3-tier scoring system sensitivity increased to 100% (14 of 14) and specificity was 96% (79 of 82).

Abbott Molecular break-apart FISH probes can be used to detect RET fusions. Laboratories can optimize cutoffs and/or testing algorithms to maximize sensitivity and specificity to ensure appropriate patients receive effective, timely therapy.
Abbott Molecular break-apart FISH probes can be used to detect RET fusions. Laboratories can optimize cutoffs and/or testing algorithms to maximize sensitivity and specificity to ensure appropriate patients receive effective, timely therapy.Cutaneous T cell lymphoma (CTCL) is a heterogeneous group of mature T cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, Mycosis Fungoides, is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary Syndrome, a leukemic form of disease is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin and blood residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from leukemic MF and SS patients, we combine T cell receptor clonotyping, with quantification of gene expression and cell surface markers at the single cell level. Our data reveals clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin-derived and blood-derived malignant T cells. Analysis of these two populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients' individual malignant profiles at the time of therapy to eliminate all sub-clones.In the past decade enormous progress has been made in the development of gene therapy for hemophilia A and B. After the first encouraging results of intravenously administered AAV-based liver-directed gene therapy in patients with severe hemophilia B were reported in 2011, many gene therapy studies have been initiated. Most of these studies, using AAV vectors with various gene constructs, showed sufficient FVIII and FIX expression in patients to significantly reduce the number of bleeds and the need for prophylaxis in the fast majority of the severe hemophilia patients. This resulted in great clinical benefit for nearly all patients. In this review we will summarize the most recent findings of reported and ongoing gene therapy trials. We will highlight the successful outcome of trials with focus on the results of recently reported phase 1 trials and preliminary results of phase 2b/3 trials for hemophilia A and B. These new reports also reveal the impact of side effects and drawbacks associated with gene therapy. We will therefore also discuss the limitations and remaining issues of the current gene therapy approaches. These issues have to be resolved before gene therapy will be widely available for the hemophilia patient population.Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. NF-kB transcription factor family is activated by two main pathways, the canonical and the alternative NF-kB activation pathways with different functions. The alternative NF-kB pathway leads to the activation of the transcriptionally active RelB NF-kB subunit. Alternative NF-kB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their ABC or GCB subtypes. RelB activity defines a new subset of DLBCL patients with a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for ABC tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-kB, thus indicating that current genetic tools to evaluate NF-kB activity in DLBCL do not provide information on the alternative NF-kB activation.
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