Promising anti-proliferative indolic benzenesulfonamides alter mechanisms with sulfonamide nitrogen substituents.

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use.

Druggability Analysis of Protein Targets for Drug Discovery to Combat .

Extensive research has been conducted to identify key proteins governing stress responses, virulence, and antimicrobial resistance, as well as to elucidate their interactions within . While these proteins hold promise as potential targets for novel strategies to control , given their critical roles in regulating the pathogen's metabolism, additional analysis is needed to further assess their druggability-the chance of being effectively bound by small-molecule inhibitors. In this work, 535 binding pockets of 46 protein targets for known drugs (mainly antimicrobials) were first analyzed to extract 13 structural features (e.

Standardized assays to monitor drug sensitivity in hematologic cancers.

The principle of drug sensitivity testing is to expose cancer cells to a library of different drugs and measure its effects on cell viability. Recent technological advances, continuous approval of targeted therapies, and improved cell culture protocols have enhanced the precision and clinical relevance of such screens. Indeed, drug sensitivity testing has proven diagnostically valuable for patients with advanced hematologic cancers.

Protein Interaction Network Analysis to Investigate Stress Response, Virulence, and Antibiotic Resistance Mechanisms in .

is a deadly and costly foodborne pathogen that has a high fatality rate in the elderly, pregnant women, and people with weakened immunity. It can survive under various stress conditions and is a significant concern for the food industry. In this work, a data analysis approach was developed with existing tools and databases and used to create individual and combined protein interaction networks to study stress response, virulence, and antimicrobial resistance and their interaction with .

screenwerk: a modular tool for the design and analysis of drug combination screens.

Motivation: There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data and generate data files that can be analyzed by synergy-finding bioinformatics applications.

Results: screenwerk is an open-source, end-to-end modular tool available as an R-package for the design and analysis of drug combination screens.

Investigation of Antimicrobial Resistance Genes in Listeria monocytogenes from 2010 through to 2021.

Antimicrobial resistance (AMR) is a serious public health issue. Due to resistance to current antibiotics and a low rate of development of new classes of antimicrobials, AMR is a leading cause of death worldwide. Listeria monocytogenes is a deadly foodborne pathogen that causes listeriosis for the immunocompromised, the elderly, and pregnant women.

Mcl-1 and Bcl-xL levels predict responsiveness to dual MEK/Bcl-2 inhibition in B-cell malignancies.

Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax.

bayesynergy: flexible Bayesian modelling of synergistic interaction effects in in vitro drug combination experiments.

The effect of cancer therapies is often tested pre-clinically via in vitro experiments, where the post-treatment viability of the cancer cell population is measured through assays estimating the number of viable cells. In this way, large libraries of compounds can be tested, comparing the efficacy of each treatment. Drug interaction studies focus on the quantification of the additional effect encountered when two drugs are combined, as opposed to using the treatments separately.

Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening.

Sarcomas are a heterogeneous group of mesenchymal orphan cancers and new treatment alternatives beyond traditional chemotherapeutic regimes are much needed. So far, tumor mutation analysis has not led to significant treatment advances, and we have attempted to bypass this limitation by performing direct drug testing of a library of 353 anti-cancer compounds that are either FDA-approved, in clinical trial, or in advanced stages of preclinical development on a panel of 13 liposarcoma cell lines. We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 -a proteasome inhibitor, GSK2126458 -a PI3K/mTOR inhibitor, JNJ-26481585 -a histone deacetylase inhibitor, triptolide-a multi-target drug, YM155 -a survivin inhibitor, and APO866 (FK866)-a nicotinamide phosphoribosyl transferase inhibitor.

Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma.

FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified , but we previously only demonstrated transient cytostatic effects when treating -amplified DDLPS cells with NVP-BGJ398. Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis and also testing efficacy . Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway.

PP2A Regulatory Subunit B55γ is a Gatekeeper of Osteoblast Maturation and Lineage Maintenance.

Bone marrow mesenchymal stem cells (BM-MSCs) mediate skeletal remodeling by differentiating into osteoblasts. However, this remodeling is impaired with aging as well as following long-term glucocorticoid treatment, resulting in osteoporosis. In this study, we report a novel factor of osteoblast differentiation-PP2A regulatory subunit B55γ.

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma.

Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines.

Tumour microenvironments induce expression of urokinase plasminogen activator receptor (uPAR) and concomitant activation of gelatinolytic enzymes.

Background: The urokinase plasminogen activator receptor (uPAR) is associated with poor prognosis in oral squamous cell carcinoma (OSCC), and increased expression of uPAR is often found at the invasive tumour front. The aim of the current study was to elucidate the role of uPAR in invasion and metastasis of OSCC, and the effects of various tumour microenvironments in these processes. Furthermore, we wanted to study whether the cells' expression level of uPAR affected the activity of gelatinolytic enzymes.

Aminated β-1,3-D-glucan has a dose-dependent effect on wound healing in diabetic db/db mice.

Inflammatory responses are common in diabetes and are operative in angiopathy, neuropathy, and wound healing. There are indications of incomplete macrophage activation in diabetes and reduced expression of growth factors. We have previously found that up to 15 topical applications of the macrophage-stimulant, aminated β-1,3-D-glucan (AG), improved wound healing in db/db mice.

Large pKa shifts of alpha-carbon acids induced by copper(II) complexes.

A series of synthetic receptors (4-6) incorporating metal ions, specifically copper(II), were examined for their ability to enhance the acidity of active methylene compounds. The copper(II) complexes were observed to reduce the pKa of 1,3-diketone carbon acids in acetonitrile by as much as 12 pKa units. The relatively large pKa reduction achieved by the complex is attributed to the electrostatic interaction between the anionic pi system of the enolate and the copper(II) ions.

Toward a stable hydroxyphosphorane.

[reaction: see text] Hydroxy-pentaoxy-phosphoranes are transient intermediates formed during the hydrolysis of various phosphoesters. Kinetic analyses support the existence of such compounds, although they are not isolated. In an attempt to create a stable example, 2 equiv of a ligand possessing a very high effective molarity were attached to a central phosphorus.