Barriers to Timely Lung Cancer Care in Early Stage Non-Small Cell Lung Cancer and Impact on Patient Outcomes.

BACKGROUND: Optimal time to treatment for early-stage lung cancer is uncertain. We examined causes of delays in care for Veterans who presented with early-stage non-small cell lung cancer (NSCLC) and whether workup time was associated with increased upstaging or all-cause mortality. METHODS: We performed a retrospective analysis of Veterans referred to our facility with radiographic stage I or II NSCLC between January 2013 to December 2017, with follow-up through October 2021. Patient demographics, tumor characteristics, time intervals of care, and reasons for delays were collected. Guideline concordance (GC) was defined as treatment within 14 weeks of abnormal image. Multivariable analyses were performed to determine association between delays in care, survival, and upstaging. RESULTS: Data from 203 Veterans were analyzed. Median time between abnormal imaging to treatment was 17.7 weeks (IQR 12.7-26.6). Only 33% of Veterans received GC care. Most common patient-related delays were: intercurrent hospitalization/comorbidity (23%), no-shows (16%) and inability to reach Veteran (17%). Most common system-related delay: lack of scheduling availability (25%). Delays associated with upstaging: transportation issues, request for coordination of appointments, and unforeseen appointment changes. Rates of upstaging did not differ between GC and discordant groups (P = .6). GC care was not an independent predictor of mortality. Post-hoc, treatment within 8 weeks was associated with lower rates of upstaging (P = .05). CONCLUSION: Although GC care did not impact survival or upstaging for early-stage NSCLC, shorter timeframes may be beneficial. Modifiable delays in care exist which may be addressed at an institutional level to improve timeliness of care.

UAS™-A Urine Preservative for Oncology Applications.

Liquid biopsy is a revolutionary tool that is gaining momentum in the field of cancer research. As a body fluid, urine can be used in non-invasive diagnostics for various types of cancer. We investigated the performance of UAS™ as a preservative for urinary analytes. Firstly, the need for urine preservation was investigated using urine samples from healthy volunteers. Secondly, the performance of UAS™ was assessed for cell-free DNA (cfDNA) and host cell integrity during storage at room temperature (RT) and after freeze-thaw cycling. Finally, UAS™ was used in a clinical setting on samples from breast and prostate cancer patients. In the absence of a preservative, urinary cfDNA was degraded, and bacterial overgrowth occurred at RT. In urine samples stored in UAS™, no microbial growth was seen, and cfDNA and cellular integrity were maintained for up to 14 days at RT. After freeze-thaw cycling, the preservation of host cell integrity and cfDNA showed significant improvements when using UAS™ compared to unpreserved urine samples. Additionally, UAS™ was found to be compatible with several commercially available isolation methods.

Association of Antithyroid Antibodies in Checkpoint Inhibitor-Associated Thyroid Immune-Related Adverse Events.

CONTEXT: The significance of thyroid peroxidase (TPOAb) and thyroglobulin antibody (TgAb) in the pathogenesis of thyroid immune-related adverse events (irAEs) is unknown. OBJECTIVE: To characterize the association of anti-thyroid antibodies with the development of thyroid immune related adverse events. METHODS: A retrospective cohort study was conducted of patients with melanoma receiving immune checkpoint inhibitor (ICI) treatment. TPOAb, TgAb, and interleukin-6 (IL-6) were measured retrospectively using tumor-banked samples at baseline and at time of diagnosis of a thyroid irAE. In euthyroid patients (without thyroid irAEs) measures were repeated 30 to 60 days after ICI commencement, which was similar to the median time to onset of thyroid irAEs in other patients. RESULTS: A total of 122 patients were included-31 remained euthyroid, 47 developed subclinical thyrotoxicosis, 37 developed overt thyrotoxicosis, and 7 developed overt hypothyroidism without preceding thyrotoxicosis. Baseline elevation of TPOAb or TgAb was present in 19 (16%) and 28 (23%) patients, respectively. Positive TPOAb or TgAb at baseline was 97% and 100% specific for eventual development of a thyroid irAE, respectively. During ICI treatment, overt thyrotoxicosis, but not other subtypes of thyroid irAE, was associated with statistically significant increases in the titer of TgAb and TPOAb. Baseline IL-6 levels were not associated with thyroid irAE onset but statistically significantly increased during treatment in patients who developed overt hypothyroidism. CONCLUSIONS: TPOAb and TgAb positivity at baseline was more prevalent in patients who developed thyroid irAEs. Statistically significant increases or new antibody positivity was observed in association with overt thyrotoxicosis. TPOAb and TgAb positivity or increases during ICI treatment may be a useful biomarker to identify patients at increased risk of thyroid irAEs, particularly overt thyrotoxicosis.

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility.

Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.

Influence of exercise intensity and duration on functional and biochemical perturbations in the human heart.

KEY POINTS: Strenuous endurance exercise induces transient functional and biochemical cardiac perturbations that persist for 24-48 h. The magnitude and time-course of exercise-induced reductions in ventricular function and increases in cardiac injury markers are influenced by the intensity and duration of exercise. In a human experimental model, exercise-induced reductions in ventricular strain and increases in cardiac troponin are greater, and persist for longer, when exercise is performed within the heavy- compared to moderate-intensity exercise domain, despite matching for total mechanical work. The results of the present study help us better understand the dose-response relationship between endurance exercise and acute cardiac stress/injury, a finding that has implications for the prescription of day-to-day endurance exercise regimes. ABSTRACT: Strenuous endurance exercise induces transient cardiac perturbations with ambiguous health outcomes. The present study investigated the magnitude and time-course of exercise-induced functional and biochemical cardiac perturbations by manipulating the exercise intensity-duration matrix. Echocardiograph-derived left (LV) and right (RV) ventricular global longitudinal strain (GLS), and serum high-sensitivity cardiac troponin (hs-cTnI) concentration, were examined in 10 males (age: 27 ± 4 years; V̇O2, peak : 4.0 ± 0.8 l min(-1) ) before, throughout (50%, 75% and 100%), and during recovery (1, 3, 6 and 24 h) from two exercise trials. The two exercise trials consisted of 90 and 120 min of heavy- and moderate-intensity cycling, respectively, with total mechanical work matched. LVGLS decreased (P < 0.01) during the 90 min trial only, with reductions peaking at 1 h post (pre: -19.9 ± 0.6%; 1 h post: -18.5 ± 0.7%) and persisting for >24 h into recovery. RVGLS decreased (P < 0.05) during both exercise trials with reductions in the 90 min trial peaking at 1 h post (pre: -27.5 ± 0.7%; 1 h post: -25.1 ± 0.8%) and persisting for >24 h into recovery. Serum hs-cTnI increased (P < 0.01) during both exercise trials, with concentrations peaking at 3 h post but only exceeding cardio-healthy reference limits (14 ng l(-1) ) in the 90 min trial (pre: 4.2 ± 2.4 ng l(-1) ; 3 h post: 25.1 ± 7.9 ng l(-1) ). Exercise-induced reductions in ventricular strain and increases in cardiac injury markers persist for 24 h following exercise that is typical of day-to-day endurance exercise training; however, the magnitude and time-course of this response can be altered by manipulating the intensity-duration matrix.

Crescerin uses a TOG domain array to regulate microtubules in the primary cilium.

Eukaryotic cilia are cell-surface projections critical for sensing the extracellular environment. Defects in cilia structure and function result in a broad range of developmental and sensory disorders. However, mechanisms that regulate the microtubule (MT)-based scaffold forming the cilia core are poorly understood. TOG domain array-containing proteins ch-TOG and CLASP are key regulators of cytoplasmic MTs. Whether TOG array proteins also regulate ciliary MTs is unknown. Here we identify the conserved Crescerin protein family as a cilia-specific, TOG array-containing MT regulator. We present the crystal structure of mammalian Crescerin1 TOG2, revealing a canonical TOG fold with conserved tubulin-binding determinants. Crescerin1's TOG domains possess inherent MT-binding activity and promote MT polymerization in vitro. Using Cas9-triggered homologous recombination in Caenorhabditis elegans, we demonstrate that the worm Crescerin family member CHE-12 requires TOG domain-dependent tubulin-binding activity for sensory cilia development. Thus, Crescerin expands the TOG domain array-based MT regulatory paradigm beyond ch-TOG and CLASP, representing a distinct regulator of cilia structure.

Using Sealed Wells to Measure Water Levels Beneath Streams and Floodplains.

The design of wells beneath streams and floodplains has often employed with tall standpipes to prevent incursion of surface water into the well during flood events. Here, an approach has been presented to minimise the infrastructure demands in these environments by sealing the well top (e.g., prevent water entering the well) and monitor the total pressure in the water column using an absolute (non-vented) pressure transducer. The sealed well design was tested using a laboratory experiment where the total pressure responses were monitored in both an unsealed and sealed well, while the water level was varied. It is observed that, whether the well is sealed or not, the total pressure at a given depth in the aquifer will be equal to that within the well. This indicates that the sealed well design is a viable alternative to tall standpipes and also facilitates installation of wells beneath streams and floodplains.

Influence of seasonal variations in sea level on the salinity regime of a coastal groundwater-fed wetland.

Seasonal variations in sea level are often neglected in studies of coastal aquifers; however, they may have important controls on processes such as submarine groundwater discharge, sea water intrusion, and groundwater discharge to coastal springs and wetlands. We investigated seasonal variations in salinity in a groundwater-fed coastal wetland (the RAMSAR listed Piccaninnie Ponds in South Australia) and found that salinity peaked during winter, coincident with seasonal sea level peaks. Closer examination of salinity variations revealed a relationship between changes in sea level and changes in salinity, indicating that sea level-driven movement of the fresh water-sea water interface influences the salinity of discharging groundwater in the wetland. Moreover, the seasonal control of sea level on wetland salinity seems to override the influence of seasonal recharge. A two-dimensional variable density model helped validate this conceptual model of coastal groundwater discharge by showing that fluctuations in groundwater salinity in a coastal aquifer can be driven by a seasonal coastal boundary condition in spite of seasonal recharge/discharge dynamics. Because seasonal variations in sea level and coastal wetlands are ubiquitous throughout the world, these findings have important implications for monitoring and management of coastal groundwater-dependent ecosystems.