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The validation and clinical bioanalysis of the Bicycle® Toxin Conjugate zelenectide pevedotin in human plasma.
Bioanalysis
January 2025
Quantitative Pharmacology, Bicycle Therapeutics, Cambridge, MA, USA.
Background: The Bicycle® toxin conjugate (BTC) zelenectide pevedotin, formerly known as BT8009, is a novel bicyclic peptide targeting the Nectin-4 tumor antigen conjugated to the cytotoxin monomethyl auristatin E (MMAE) via a valine-citrulline cleavable linker. Zelenectide pevedotin is currently being investigated in a Phase 1/2 (Duravelo-1, NCT04561362) clinical trial to determine safety and efficacy in patients with tumors associated with Nectin-4 expression. A simple regulated bioanalytical assay was developed to quantify intact zelenectide pevedotin in patient plasma samples.
View Article and Find Full Text PDFChromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency.
View Article and Find Full Text PDFHere we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.
View Article and Find Full Text PDFLate-Stage Reshaping of Phage-Displayed Libraries to Macrocyclic and Bicyclic Landscapes using a Multipurpose Linchpin.
J Am Chem Soc
January 2025
Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
Genetically encoded libraries (GEL) are increasingly being used for the discovery of ligands for "undruggable" targets that cannot be addressed with small molecules. Foundational GEL platforms like phage-, yeast-, ribosome-, and mRNA-display have enabled the display of libraries composed of 20 natural amino acids (20AA). Unnatural amino acids (UAA) and chemical post-translational modification (cPTM) expanded GEL beyond the 20AA space to yield unnatural linear, cyclic, and bicyclic peptides.
View Article and Find Full Text PDFMuscle-Fiber Typology Is Associated With Sprint-Cycling Characteristics in World-Class and Elite Track Cyclists.
Int J Sports Physiol Perform
January 2025
Griffith Sports Science, Griffith University, Gold Coast, QLD, Australia.
Purpose: Identifying the determinants of performance is fundamental to talent identification and individualizing training prescription. Consequently, the aim of this study was to determine whether estimated muscle typology is associated with the key mechanical characteristics of track sprint cycling.
Methods: Sixteen world-class and elite track cyclists (n = 7 female) completed a laboratory session wherein torque-cadence and power-cadence profiles were constructed to determine maximal power output (Pmax), optimal cadence (Fopt), and maximal cadence (Fmax), and fatigue rate per pedal stroke was determined during a 15-second maximal sprint at Fopt.
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