Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

PurposeTo date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.MethodsWe assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.ResultsOverall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification.ConclusionEGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study

Intragenic alternative splicing coordination is essential for Caenorhabditis elegans slo-1 gene function

Alternative splicing is critical for diversifying eukaryotic proteomes, but the rules governing and coordinating splicing events among multiple alternate splice sites within individual genes are not well understood. We developed a quantitative PCR-based strategy to quantify the expression of the 12 transcripts encoded by the Caenorhabditis elegans slo-1 gene, containing three alternate splice sites. Using conditional probability-based models, we show that splicing events are coordinated across these sites. Further, we identify a point mutation in an intron adjacent to one alternate splice site that disrupts alternative splicing at all three sites. This mutation leads to aberrant synaptic transmission at the neuromuscular junction. In a genomic survey, we found that a UAAAUC element disrupted by this mutation is enriched in introns flanking alternate exons in genes with multiple alternate splice sites. These results establish that proper coordination of intragenic alternative splicing is essential for normal physiology of slo-1 in vivo and identify putative specialized cis-regulatory elements that regulate the coordination of intragenic alternative splicing

Age of First Overweight and Obesity, COVID-19 and Long COVID in Two British Birth Cohorts

Longer exposure to obesity, and thus a longer period in an inflamed state, may increase susceptibility to infectious diseases and worsen severity. Previous cross-sectional work finds higher BMI is related to worse COVID-19 outcomes, but less is known about associations with BMI across adulthood. To examine this, we used body mass index (BMI) collected through adulthood in the 1958 National Child Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Participants were grouped by the age they were first overweight (> 25 kg/m2) and obese (> 30 kg/m2). Logistic regression was used to assess associations with COVID-19 (self-reported and serology-confirmed), severity (hospital admission and contact with health services) and long-COVID reported at ages 62 (NCDS) and 50 (BCS70). An earlier age of obesity and overweight, compared to those who never became obese or overweight, was associated with increased odds of adverse COVID-19 outcomes, but results were mixed and often underpowered. Those with early exposure to obesity were over twice as likely in NCDS (odds ratio (OR) 2.15, 95% confidence interval (CI) 1.17-4.00) and three times as likely in BCS70 (OR 3.01, 95% CI 1.74-5.22) to have long COVID. In NCDS they were also over four times as likely to be admitted to hospital (OR 4.69, 95% CI 1.64-13.39). Most associations were somewhat explained by contemporaneous BMI or reported health, diabetes or hypertension; however, the association with hospital admission in NCDS remained. An earlier age of obesity onset is related to COVID-19 outcomes in later life, providing evidence of the long-term impact of raised BMI on infectious disease outcomes in midlife

Coherent Backscattering of Ultracold Atoms

We report on the direct observation of coherent backscattering (CBS) of ultracold atoms, in a quasi-two-dimensional configuration. Launching atoms with a well-defined momentum in a laser speckle disordered potential, we follow the progressive build up of the momentum scattering pattern, consisting of a ring associated with multiple elastic scattering, and the CBS peak in the backward direction. Monitoring the depletion of the initial momentum component and the formation of the angular ring profile allows us to determine microscopic transport quantities. The time resolved evolution of the CBS peak is studied and is found a fair agreement with predictions, at long times as well as at short times. The observation of CBS can be considered a direct signature of coherence in quantum transport of particles in disordered media. It is responsible for the so called weak localization phenomenon, which is the precursor of Anderson localization.Comment: 5 pages, 4 figure

Vector-soliton collision dynamics in nonlinear optical fibers

We consider the interactions of two identical, orthogonally polarized vector solitons in a nonlinear optical fiber with two polarization directions, described by a coupled pair of nonlinear Schroedinger equations. We study a low-dimensional model system of Hamiltonian ODE derived by Ueda and Kath and also studied by Tan and Yang. We derive a further simplified model which has similar dynamics but is more amenable to analysis. Sufficiently fast solitons move by each other without much interaction, but below a critical velocity the solitons may be captured. In certain bands of initial velocities the solitons are initially captured, but separate after passing each other twice, a phenomenon known as the two-bounce or two-pass resonance. We derive an analytic formula for the critical velocity. Using matched asymptotic expansions for separatrix crossing, we determine the location of these "resonance windows." Numerical simulations of the ODE models show they compare quite well with the asymptotic theory.Comment: 32 pages, submitted to Physical Review

The impact of using the Web in a mixed-mode follow-up of a longitudinal birth cohort study: Evidence from the National Child Development Study

A sequential mixed-mode data collection, online-to-telephone, was introduced into the National Child Development Study for the first time at the study's age 55 sweep in 2013. The study included a small experiment, whereby a randomised subset of study members was allocated to a single mode, telephone-only interview, in order to test for the presence of mode effects on participation and measurement. Relative to telephone-only, the offer of the Web increased overall participation rates by 5.0 percentage points (82.8% vs. 77.8%; 95% confidence interval for difference: 2.7% to 7.3%). Differences attributable to mode of interview were detected in levels of item non-response and response values for a limited number of questions. Most notably, response by Web (relative to telephone) was found to have increased the likelihood of non-response to questions relating to pay and other financial matters, and increased the likelihood of ‘less desirable’ responses. For example, response by Web resulted in the reporting of more units of alcohol consumed, and more negative responses to subjective questions such as self-rated health, self-rated financial status and well-being. As there was evidence of mode effects, there is the potential for biases in some analyses, unless appropriate techniques are utilised to correct for these