Excessive concentrations of kinase inhibitors in translational studies impede effective drug repurposing.

Drug repositioning seeks to leverage existing clinical knowledge to identify alternative clinical settings for approved drugs. However, repositioning efforts fail to demonstrate improved success rates in late-stage clinical trials. Focusing on 11 approved kinase inhibitors that have been evaluated in 139 repositioning hypotheses, we use data mining to characterize the state of clinical repurposing.

Nanoscale coordination polymers enabling antioxidants inhibition for enhanced chemodynamic therapy.

Reactive oxygen species (ROS) generation to induce cell death is an effective strategy for cancer therapy. In particular, chemodynamic therapy (CDT), using Fenton-type reactions to generate highly cytotoxic hydroxyl radical (•OH), is a promising treatment modality. However, the therapeutic efficacy of ROS-based cancer treatment is still limited by some critical challenges, such as overexpression of enzymatic and non-enzymatic antioxidants by tumor cells, as well as the low tumor targeting efficiency of therapeutic agents.

An Ultrafast One-Step Quantitative Reverse Transcription-Polymerase Chain Reaction Assay for Detection of SARS-CoV-2.

We developed an ultrafast one-step RT-qPCR assay for SARS-CoV-2 detection, which can be completed in only 30 min on benchtop CFX96. The assay significantly reduces the running time of conventional RT-qPCR: reduced RT step from 10 to 1 min, and reduced the PCR cycle of denaturation from 10 to 1 s and extension from 30 to 1 s. A cohort of 60 nasopharyngeal swab samples testing showed that the assay had a clinical sensitivity of 100% and a clinical specificity of 100%.

Emerging methods in biomarker identification for extracellular vesicle-based liquid biopsy.

Extracellular vesicles (EVs) are released by many cell types and distributed within various biofluids. EVs have a lipid membrane-confined structure that allows for carrying unique molecular information originating from their parent cells. The species and quantity of EV cargo molecules, including nucleic acids, proteins, lipids, and metabolites, may vary largely owing to their parent cell types and the pathophysiologic status.

The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Autoimmune Disorders.

Extracellular vesicles (EVs) are important players in autoimmune diseases, both in disease pathogenesis and as potential treatments. EVs can transport autoimmune triggers throughout the body, facilitating the process of antigen presentation. Understanding the link between cellular stress and EV biogenesis and intercellular trafficking will advance our understanding of autoimmune diseases.

The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning.

Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments.

Mechanoresponsive stem cells to target cancer metastases through biophysical cues.

Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model.

mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph and Ph-like B-ALL.

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes.

Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis.

Systemic administration of mesenchymal stem cells (MSCs) affords the potential to ameliorate the symptoms of Multiple Sclerosis (MS) in both preclinical and clinical studies. However, the efficacy of MSC-based therapy for MS likely depends on the number of cells that home to inflamed tissues and on the controlled production of paracrine and immunomodulatory factors. Previously, we reported that engineered MSCs expressing P-selectin glycoprotein ligand-1 (PSGL-1) and Sialyl-Lewis(x) (SLeX) via mRNA transfection facilitated the targeted delivery of anti-inflammatory cytokine interleukin-10 (IL-10) to inflamed ear.

Exogenous marker-engineered mesenchymal stem cells detect cancer and metastases in a simple blood assay.

Introduction: Mesenchymal stem cells (MSCs) are adult multipotent stem cells that possess regenerative and immunomodulatory properties. They have been widely investigated as therapeutic agents for a variety of disease conditions, including tissue repair, inflammation, autoimmunity, and organ transplantation. Importantly, systemically infused MSCs selectively home to primary and metastatic tumors, though the molecular mechanisms of tumor tropism of MSCs remain incompletely understood.

Digital quantification of miRNA directly in plasma using integrated comprehensive droplet digital detection.

Quantification of miRNAs in blood can be potentially used for early disease detection, surveillance monitoring and drug response evaluation. However, quantitative and robust measurement of miRNAs in blood is still a major challenge in large part due to their low concentration and complicated sample preparation processes typically required in conventional assays. Here, we present the 'Integrated Comprehensive Droplet Digital Detection' (IC 3D) system where the plasma sample containing target miRNAs is encapsulated into microdroplets, enzymatically amplified and digitally counted using a novel, high-throughput 3D particle counter.

Pharmacokinetics in rats and tissue distribution in mouse of berberrubine by UPLC-MS/MS.

Berberrubine is an isoquinoline alkaloid isolated from Berberis vulgaris L, and it is readily derived from berberine. In this study, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of berberrubine in rat plasma and mouse tissue has been developed. Magnoflorine was employed as an internal standard (IS), and liquid-liquid extraction by ethyl acetate was used for sample preparation.

mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells.

High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors.

Nucleic acid aptamers in cancer research, diagnosis and therapy.

Aptamers are single-stranded DNA or RNA oligomers, identified from a random sequence pool, with the ability to form unique and versatile tertiary structures that bind to cognate molecules with superior specificity. Their small size, excellent chemical stability and low immunogenicity enable them to rival antibodies in cancer imaging and therapy applications. Their facile chemical synthesis, versatility in structural design and engineering, and the ability for site-specific modifications with functional moieties make aptamers excellent recognition motifs for cancer biomarker discovery and detection.

Aptamer technology for tracking cells' status & function.

In fields such as cancer biology and regenerative medicine, obtaining information regarding cell bio-distribution, tropism, status, and other cellular functions are highly desired. Understanding cancer behaviors including metastasis is important for developing effective cancer treatments, while assessing the fate of therapeutic cells following implantation is critical to validate the efficacy and efficiency of the therapy. For visualization purposes with medical imaging modalities (e.

Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function.

Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes.