Impact of PROphet Test in Changing Physicians' Therapeutic Decision-Making for Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer.

Purpose: Immune Checkpoint Inhibitor (ICI) regimens are approved for first-line treatment of metastatic nononcogene-driven NSCLC. Guidelines do not differentiate which patients with PD-L1 ≥ 50% should receive ICI monotherapy. The clinically validated PROphet NSCLC plasma proteomic-based test is designed to inform this therapeutic decision.

Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.

Purpose: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions.

Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy.

Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.

Analytical validation of the PROphet test for treatment decision-making guidance in metastatic non-small cell lung cancer.

The blood proteome, consisting of thousands of proteins engaged in various biological processes, acts as a valuable source of potential biomarkers for various medical applications. PROphet is a plasma proteomics-based test that serves as a decision-support tool for non-small cell lung cancer (NSCLC) patients, combining proteomic profiling using SomaScan technology and subsequent computational algorithm. PROphet was implemented as a laboratory developed test (LDT).

Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapy landscape due to long-term benefits in patients with advanced metastatic disease. However, robust predictive biomarkers for response are still lacking and treatment resistance is not fully understood.

Methods: We profiled approximately 800 pre-treatment and on-treatment plasma proteins from 143 ICI-treated patients with non-small cell lung cancer (NSCLC) using ELISA-based arrays.

Assessment of assumptions underlying models of prokaryotic pangenome evolution.

Background: The genomes of bacteria and archaea evolve by extensive loss and gain of genes which, for any group of related prokaryotic genomes, result in the formation of a pangenome with the universal, asymmetrical U-shaped distribution of gene commonality. However, the evolutionary factors that define the specific shape of this distribution are not thoroughly understood.

Results: We investigate the fit of simple models of genome evolution to the empirically observed gene commonality distributions and genome intersections for 33 groups of closely related bacterial genomes.

Crossing fitness valleys via double substitutions within codons.

Background: Single nucleotide substitutions in protein-coding genes can be divided into synonymous (S), with little fitness effect, and non-synonymous (N) ones that alter amino acids and thus generally have a greater effect. Most of the N substitutions are affected by purifying selection that eliminates them from evolving populations. However, additional mutations of nearby bases potentially could alleviate the deleterious effect of single substitutions, making them subject to positive selection.

Gene gain and loss push prokaryotes beyond the homologous recombination barrier and accelerate genome sequence divergence.

Bacterial and archaeal evolution involve extensive gene gain and loss. Thus, phylogenetic trees of prokaryotes can be constructed both by traditional sequence-based methods (gene trees) and by comparison of gene compositions (genome trees). Comparing the branch lengths in gene and genome trees with identical topologies for 34 clusters of closely related bacterial and archaeal genomes, we show here that terminal branches of gene trees are systematically compressed compared to those of genome trees.

Multiple Sequence Alignment Averaging Improves Phylogeny Reconstruction.

The classic methodology of inferring a phylogenetic tree from sequence data is composed of two steps. First, a multiple sequence alignment (MSA) is computed. Then, a tree is reconstructed assuming the MSA is correct.

Estimation of universal and taxon-specific parameters of prokaryotic genome evolution.

The results of our recent study on mathematical modeling of microbial genome evolution indicate that, on average, genomes of bacteria and archaea evolve in the regime of mutation-selection balance defined by positive selection coefficients associated with gene acquisition that is counter-acted by the intrinsic deletion bias. This analysis was based on the strong assumption that parameters of genome evolution are universal across the diversity of bacteria and archaea, and yielded extremely low values of the selection coefficient. Here we further refine the modeling approach by taking into account evolutionary factors specific for individual groups of microbes using two independent fitting strategies, an ad hoc hard fitting scheme and a mixture model.

Theory of prokaryotic genome evolution.

Bacteria and archaea typically possess small genomes that are tightly packed with protein-coding genes. The compactness of prokaryotic genomes is commonly perceived as evidence of adaptive genome streamlining caused by strong purifying selection in large microbial populations. In such populations, even the small cost incurred by nonfunctional DNA because of extra energy and time expenditure is thought to be sufficient for this extra genetic material to be eliminated by selection.

Neck motion kinematics: an inter-tester reliability study using an interactive neck VR assessment in asymptomatic individuals.

Background And Purpose: The use of virtual reality (VR) for assessment and intervention of neck pain has previously been used and shown reliable for cervical range of motion measures. Neck VR enables analysis of task-oriented neck movement by stimulating responsive movements to external stimuli. Therefore, the purpose of this study was to establish inter-tester reliability of neck kinematic measures so that it can be used as a reliable assessment and treatment tool between clinicians.

GUIDANCE2: accurate detection of unreliable alignment regions accounting for the uncertainty of multiple parameters.

Inference of multiple sequence alignments (MSAs) is a critical part of phylogenetic and comparative genomics studies. However, from the same set of sequences different MSAs are often inferred, depending on the methodologies used and the assumed parameters. Much effort has recently been devoted to improving the ability to identify unreliable alignment regions.

Balance maintenance as an acquired motor skill: Delayed gains and robust retention after a single session of training in a virtual environment.

Does the learning of a balance and stability skill exhibit time-course phases and transfer limitations characteristic of the acquisition and consolidation of voluntary movement sequences? Here we followed the performance of young adults trained in maintaining balance while standing on a moving platform synchronized with a virtual reality road travel scene. The training protocol included eight 3 min long iterations of the road scene. Center of Pressure (CoP) displacements were analyzed for each task iteration within the training session, as well as during tests at 24h, 4 weeks and 12 weeks post-training to test for consolidation phase ("offline") gains and assess retention.

Visual and auditory synchronization deficits among dyslexic readers as compared to non-impaired readers: a cross-correlation algorithm analysis.

Visual and auditory temporal processing and crossmodal integration are crucial factors in the word decoding process. The speed of processing (SOP) gap (Asynchrony) between these two modalities, which has been suggested as related to the dyslexia phenomenon, is the focus of the current study. Nineteen dyslexic and 17 non-impaired University adult readers were given stimuli in a reaction time (RT) procedure where participants were asked to identify whether the stimulus type was only visual, only auditory or crossmodally integrated.

Enhanced reading by training with imposed time constraint in typical and dyslexic adults.

Poor reading skills of developmental dyslexics persist into adulthood with standard remediation protocols having little effect. Nevertheless, reading improves if readers are induced to read faster. Here we show that this improvement can be enhanced by training.

A working memory deficit among dyslexic readers with no phonological impairment as measured using the n-back task: an fNIR study.

Data indicated that dyslexic individuals exhibited difficulties on tasks involving Working Memory (WM). Previous studies have suggested that these deficits stem from impaired processing in the Phonological Loop (PL). The PL impairment was connected to poor phonological processing.

Differences in learning volitional (manual) and non-volitional (posture) aspects of a complex motor skill in young adult dyslexic and skilled readers.

The 'Cerebellar Deficit Theory' of developmental dyslexia proposes that a subtle developmental cerebellar dysfunction leads to deficits in attaining 'automatic' procedures and therefore manifests as subtle motor impairments (e.g., balance control, motor skill learning) in addition to the reading and phonological difficulties.

A functional near-infrared spectroscopy study of lexical decision task supports the dual route model and the phonological deficit theory of dyslexia.

The dual route model (DRM) of reading suggests two routes of reading development: the phonological and the orthographic routes. It was proposed that although the two routes are active in the process of reading; the first is more involved at the initial stages of reading acquisition, whereas the latter needs more reading training to mature. A number of studies have shown that deficient phonological processing is a core deficit in developmental dyslexia.

Frontal lobe role in simple arithmetic calculations: an fNIR study.

This study aimed to affirm the use of functional near-infrared spectroscopy (fNIR) in examining frontal lobe role during automatic (i.e., requires retrieval from long-term memory) and method-based (i.

Nonspecific transcription-factor-DNA binding influences nucleosome occupancy in yeast.

Quantitative understanding of the principles regulating nucleosome occupancy on a genome-wide level is a central issue in eukaryotic genomics. Here, we address this question using budding yeast, Saccharomyces cerevisiae, as a model organism. We perform a genome-wide computational analysis of the nonspecific transcription factor (TF)-DNA binding free-energy landscape and compare this landscape with experimentally determined nucleosome-binding preferences.

DNA sequence correlations shape nonspecific transcription factor-DNA binding affinity.

Transcription factors (TFs) are regulatory proteins that bind DNA in promoter regions of the genome and either promote or repress gene expression. Here, we predict analytically that enhanced homooligonucleotide sequence correlations, such as poly(dA:dT) and poly(dC:dG) tracts, statistically enhance nonspecific TF-DNA binding affinity. This prediction is generic and qualitatively independent of microscopic parameters of the model.

Anomalous decay of a prepared state due to non-Ohmic coupling to the continuum.

We study the decay of a prepared state E0 into a continuum {Ek} in the case of non-Ohmic models. This means that the coupling is Vk,|proportional|Ek-E0s-1 with s not equal 1. We find that irrespective of model details there is a universal generalized Wigner time t0 that characterizes the decay of the survival probability P0(t).