Lipid-Modulated, Graduated Inhibition of N-Glycosylation Pathway Priming Suggests Wide Tolerance of ER Proteostasis to Stress.

Protein N-glycosylation is a cotranslational modification that takes place in the endoplasmic reticulum (ER). Disruption of this process can result in accumulation of misfolded proteins, known as ER stress. In response, the unfolded protein response (UPR) restores proteostasis or responds by controlling cellular fate, including increased expression of activating transcription factor 4 (ATF4) that can lead to apoptosis.

A Phase II Trial of Onapristone and Fulvestrant for Patients With ER+ and HER2- Metastatic Breast Cancer.

Background: The SMILE study is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone, in combination with fulvestrant as second-line therapy for patients with ER+, PgR+/-, HER2- metastatic breast cancer. This study was terminated early and herein, we report patient characteristics, and outcomes.

Methods: Eligibility criteria included disease progression on ≥2 lines of prior therapy, ECOG performance status ≤ 2, measurable disease per RECIST 1.

Identification of a novel nuclease activity in human DDX49 helicase.

Human DDX49 is an emerging target in cancer progression and retroviral diseases through its essential roles in nucleolar RNA processing. Here, we identify nuclease activity of human DDX49, which requires active site aspartate residues within a conserved region of metazoan DDX49s that is absent from yeast and archaeal DDX49 homologues. We provide evidence that DDX49 nuclease activity is facilitated by its helicase activity.

Pharmacokinetics of Tarlatamab, a Delta-Like Ligand-3 (DLL3) Targeted Half-Life Extended Bispecific T-Cell Engager (BiTE) Immunotherapy in Adult Patients with Previously Treated Small-Cell Lung Cancer: Results from DeLLphi-300, a Phase I Multiple-Dose-Escalation Study.

Background: Tarlatamab binds to delta-like ligand 3 on cancer cells and cluster of differentiation-3 on T cells, leading to T-cell-mediated tumor lysis, and has demonstrated a promising safety and efficacy profile in patients with previously treated small-cell lung cancer (SCLC). Here, we present pharmacokinetic results from DeLLphi-300 (NCT03319940), an ongoing international, open-label, first-in-human study in previously treated adult patients with SCLC.

Methods: Multiple escalating doses of tarlatamab were administered every 2 weeks (Q2W; 0.

Evaluating experimental, knowledge-based and computational cocrystal screening methods to advance drug-drug cocrystal fixed-dose combination development.

Fixed-dose combinations (FDCs) offer significant advantages to patients and the pharmaceutical industry alike through improved dissolution profiles, synergistic effects and extended patent lifetimes. Identifying whether two active pharmaceutical ingredients have the potential to form a drug-drug cocrystal (DDC) or interact is an essential step in determining the most suitable type of FDC to formulate. The lack of coherent strategies to determine if two active pharmaceutical ingredients that can be co-administered can form a cocrystal, has significantly impacted DDC commercialisation.