Semi-mechanistic efficacy model for PARP + ATR inhibitors-application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs.

Background: Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges.

Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination.

PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.

DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells.

First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors.

Background: Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach.

Evaluation of the Adhesion Strength of Ultrathin Gold Coatings on Substrates of Soda-Lime Glass and Cyclo-Olefin-Polymer by Cross-Cut and Scratch Tests under the Influence of a Thermal Shock Test for Use in Biosensors.

The current demand for highly sensitive, optical sensors in biodiagnostics has prompted the development of ultrathin metal coatings on a range of substrates. Given the potential attenuation of the signal from a plasmonic sensor for the detection of fluorescent molecules when an adhesion layer between the substrate and coating is employed, this study examines the impact of various factors on the adhesion strength between gold coatings and substrates comprising glass and cyclo-olefin-polymer (COP). The objective is to identify potential configurations for high adhesion strength, thereby eliminating the need for an adhesion layer in the fabrication of optical sensors with gold coatings for diagnostic applications or to utilize a minimal adhesion layer thickness.

Challenges and Current Trends in Preventing Antimicrobial Resistance in EU Water Law Context.

The increasing consumption of pharmaceuticals, including antibiotics, and their improper disposal have resulted in both pharmaceuticals and their metabolites being released into the environment, where they pose a risk to both ecosystems and human health. One of the most serious threats to public health associated with the presence of antibiotics in the environment is antimicrobial resistance (AMR). In order to combat AMR, the legal aspect of water protection becomes a critical area of action.