The differential prognostic implications of PD-L1 expression in the outcomes of Filipinos with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors.

Background: The tumor immune microenvironment influences tumor evolution in non-small cell lung cancer (NSCLC). Yet, the prognostic value of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor (EGFR)-mutant NSCLC remains controversial. Additionally, prognostic studies in Filipinos with EGFR-mutant NSCLC remain unexplored to this day. Methods: We prospectively studied the outcomes of EGFR-mutant NSCLC in Filipino cohort, and retrospectively verified the survival trend using The Cancer Genome Atlas (TCGA) cohort. Kaplan-Meier method and generalized linear regression were used to assess survival. Expression and DNA methylation of cluster of differentiation 274 (CD274, gene that codes for PD-L1) were examined from TCGA tumor profiles. Pearson's correlation was used to correlate PD-L1 expression with outcomes associated with occurrence of EGFR mutations, tyrosine kinase inhibitor (TKI) types, and programmed cell death protein 1 (PD-1) expression. Proteome network analysis was used to examine the correlation between drug resistance and PD-L1. Results: PD-L1 positivity was associated with significantly longer progression-free survival (PFS; P=0.0096) but had a significantly contrasting influence in the overall survival (OS; P=0.0011). PD-L1 positivity (in both protein and RNA) was associated with longer median OS (mOS) in exon21 L858R, whereas, negativity was associated with longer mOS in exon19 deletion (exon19del). Stratification (high, low, negative) of PD-L1 expression lacked significant prognostic value (all P>0.05). PD-L1/CD274 expression (P<0.05) and DNA methylation (P<0.001) vary significantly among NSCLC subtypes and in different disease stages. Erlotinib treatment produced the longest median progression-free survival (mPFS; 874 days) relative to other EGFR-TKIs (137-311 days). PD-L1 lacked a significant correlation with EGFR-TKIs. Consistent with the immune-regulation activities of PD-1, higher expression leads to relatively shorter mOS. PD-1 correlated positively with PD-L1 expression and occurrence of exon21 L858R. Conclusions: PD-L1 differentially influenced the outcomes of Filipinos with EGFR-mutant NSCLC. NSCLC subtypes, disease stage, and PD-1 expression may impact the collective outcomes associated with PD-L1 and EGFR-sensitizing mutations.

Publishing in education: A parallel session at the IUBMB/PSBMB 2019 "Harnessing Interdisciplinary Education in Biochemistry and Molecular Biology" conference.

Ensuring currency with trends, knowledge, and understanding of teaching and learning is essential for all educators. Researching learning and teaching is an enormous field which can range from examining the practical impact of new classes to research into the processes of learning. The "Publishing in Education" conference session discussed some of the approaches and outcomes of researching and publishing in education.

A History of Molecular Chaperone Structures in the Protein Data Bank.

Thirty years ago a class of proteins was found to prevent the aggregation of Rubisco. These proteins' ability to prevent unwanted associations led to their being called chaperones. These chaperone proteins also increased in expression as a response to heat shock, hence their label as heat shock proteins (Hsps). However, neither label encompasses the breadth of these proteins' functional capabilities. The term "unfoldases" has been proposed, as this basic function is shared by most members of this protein family. Onto this is added specializations that allow the different family members to perform various cellular functions. This current article focuses on the resolved structural bases for these functions. It reviews the currently available molecular structures in the Protein Data Bank for several classes of Hsps (Hsp60, Hsp70, Hsp90, and Hsp104). When possible, it discusses the complete structures for these proteins, and the types of molecular machines to which they have been assigned. The structures of domains and the associated functions are discussed in order to illustrate the rationale for the proposed unfoldase function.

The Hsp40 J-domain modulates Hsp70 conformation and ATPase activity with a semi-elliptical spring.

Regulatory protein interactions are commonly attributed to lock-and-key associations that bring interacting domains together. However, studies in some systems suggest that regulation is not achieved by binding interactions alone. We report our investigations on specific physical characteristics required of the Hsp40 J-domain to stimulate ATP hydrolysis in the Hsp40-Hsp70 molecular chaperone machine. Biophysical analysis using isothermal titration calorimetry, and nuclear magnetic resonance spectroscopy reveals the importance of helix rigidity for the maintenance of Hsp40 function. Our results suggest that the functional J-domain acts like a semi-elliptical spring, wherein the resistance to bending upon binding to the Hsp70 ATPase modulates the ATPase domain conformational change and promotes ATP hydrolysis.