Timeliness of surgery for early-stage lung cancer: Patient factors and predictors.

Objectives: Time-to-treatment initiation is an important consideration for patients undergoing thoracic surgery for early-stage lung cancer because delays have the potential to adversely affect outcomes. This study seeks to quantify time-to-treatment initiation for patients with clinical stage I lung cancer, explore patient factors and predictors that lead to an increased time-to-treatment initiation, and compare surgeon perception of appropriate time-to-treatment initiation to the results. Methods: Time-to-treatment initiation was determined for patients enrolled in the Mount Sinai Initiative for Early Lung Cancer Research on Treatment study who underwent surgical resection for clinical stage I lung cancer between March 2016 and December 2021. The following dates were determined: (1) date of first suspicious radiologic imaging, (2) date of first biopsy, and (3) date of surgery. A total of 15 thoracic surgeons who participated in the Mount Sinai Initiative for Early Lung Cancer Research on Treatment were assessed on their perception on time-to-treatment initiation. Results: For 638 patients, median time from first suspicious imaging findings to biopsy was 40 days, biopsy to surgery was 37 days, and suspicious imaging to surgery was 84 days. Significant factors that resulted in longer time-to-treatment initiation in the multivariate analysis were African American or Black race (P = .005), vascular disease (P = .01), and median household income less than $75,000 (P = .04). Although the surgeon's perception was that the average time from biopsy to surgery was 28 days, it was longer for 63.5% of participants; surgeon perception of maximum time between diagnosis and surgery was 84 days and longer for 28.7% of participants. Conclusions: Patient factors such as race, income, and comorbidities were found to have differences in time-to-treatment initiation. Delays to surgery exceeded the expectations of thoracic surgeons.

Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity.

Functional output of the hippocampus, a brain region subserving memory function, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular events involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in plasticity processes in the hippocampus, a role that decreases with brain aging as expression is lost. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. Consistent with the accumulation of extracellular matrix (ECM) in the hippocampus we observe with aging, we find that TIMP2 acts to reduce accumulation of ECM around synapses in the hippocampus. Moreover, its deletion results in hindrance of newborn neuron migration through a denser ECM network. A novel conditional TIMP2 knockout (KO) model reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.

Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice.

Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. Here, we report that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum reveals differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings uncover a cell-type-specific impact of the loss of fragile X messenger ribonucleoprotein (FMRP) on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.

The presence of circulating genetically abnormal cells in blood predicts risk of lung cancer in individuals with indeterminate pulmonary nodules.

PURPOSE: Computed tomography is the standard method by which pulmonary nodules are detected. Greater than 40% of pulmonary biopsies are not lung cancer and therefore not necessary, suggesting that improved diagnostic tools are needed. The LungLB™ blood test was developed to aid the clinical assessment of indeterminate nodules suspicious for lung cancer. LungLB™ identifies circulating genetically abnormal cells (CGACs) that are present early in lung cancer pathogenesis. METHODS: LungLB™ is a 4-color fluorescence in-situ hybridization assay for detecting CGACs from peripheral blood. A prospective correlational study was performed on 151 participants scheduled for a pulmonary nodule biopsy. Mann-Whitney, Fisher's Exact and Chi-Square tests were used to assess participant demographics and correlation of LungLB™ with biopsy results, and sensitivity and specificity were also evaluated. RESULTS: Participants from Mount Sinai Hospital (n = 83) and MD Anderson (n = 68), scheduled for a pulmonary biopsy were enrolled to have a LungLB™ test. Additional clinical variables including smoking history, previous cancer, lesion size, and nodule appearance were also collected. LungLB™ achieved 77% sensitivity and 72% specificity with an AUC of 0.78 for predicting lung cancer in the associated needle biopsy. Multivariate analysis found that clinical and radiological factors commonly used in malignancy prediction models did not impact the test performance. High test performance was observed across all participant characteristics, including clinical categories where other tests perform poorly (Mayo Clinic Model, AUC = 0.52). CONCLUSION: Early clinical performance of the LungLB™ test supports a role in the discrimination of benign from malignant pulmonary nodules. Extended studies are underway.

Structure, Function, and Molecular Landscapes of the Aging Retina.

Because the central nervous system is largely nonrenewing, neurons and their synapses must be maintained over the lifetime of an individual to ensure circuit function. Age is a dominant risk factor for neural diseases, and declines in nervous system function are a common feature of aging even in the absence of disease. These alterations extend to the visual system and, in particular, to the retina. The retina is a site of clinically relevant age-related alterations but has also proven to be a uniquely approachable system for discovering principles that govern neural aging because it is well mapped, contains diverse neuron types, and is experimentally accessible. In this article, we review the structural and molecular impacts of aging on neurons within the inner and outer retina circuits. We further discuss the contribution of non-neuronal cell types and systems to retinal aging outcomes. Understanding how and why the retina ages is critical to efforts aimed at preventing age-related neural decline and restoring neural function.

APOE4 confers transcriptomic and functional alterations to primary mouse microglia.

Common genetic variants in more than forty loci modulate risk for Alzheimer's disease (AD). AD risk alleles are enriched within enhancers active in myeloid cells, suggesting that microglia, the brain-resident macrophages, may play a key role in the etiology of AD. A major genetic risk factor for AD is Apolipoprotein E (APOE) genotype, with the ε4/ε4 (E4) genotype increasing risk for AD by approximately 15 fold compared to the most common ε3/ε3 (E3) genotype. However, the impact of APOE genotype on microglial function has not been thoroughly investigated. To address this, we cultured primary microglia from mice in which both alleles of the mouse Apoe gene have been humanized to encode either human APOE ε3 or APOE ε4. Relative to E3 microglia, E4 microglia exhibit altered morphology, increased endolysosomal mass, increased cytokine/chemokine production, and increased lipid and lipid droplet accumulation at baseline. These changes were accompanied by decreased translation and increased phosphorylation of eIF2ɑ and eIF2ɑ-kinases that participate in the integrated stress response, suggesting that E4 genotype leads to elevated levels of cellular stress in microglia relative to E3 genotype. Using live-cell imaging and flow cytometry, we also show that E4 microglia exhibited increased phagocytic uptake of myelin and other substrates compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential enrichment of genes in interferon signaling, extracellular matrix and translation-related pathways was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Together, our results suggest E4 genotype confers several important functional alterations to microglia even prior to myelin challenge, providing insight into the molecular and cellular mechanisms by which APOE4 may increase risk for AD.

Genome-wide screen identifies a novel prognostic signature for breast cancer survival.

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion, cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.

A systematic review of technology-based interventions for unintentional injury prevention education and behaviour change.

OBJECTIVE: The aims of this literature review are to (1) summarise how computer and mobile technology-based health behaviour change applications have been evaluated in unintentional injury prevention, (2) describe how these successes can be applied to injury-prevention programmes in the future and (3) identify research gaps. METHODS: Studies included in this systematic review were education and behaviour change intervention trials and programme evaluations in which the intervention was delivered by either a computer or mobile technology and addressed an unintentional injury prevention topic. Articles were limited to those published in English and after 1990. RESULTS: Among the 44 technology-based injury-prevention studies included in this review, 16 studies evaluated locally hosted software programmes, 4 studies offered kiosk-based programmes, 11 evaluated remotely hosted internet programmes, 2 studies used mobile technology or portable devices and 11 studies evaluated virtual-reality interventions. Locally hosted software programmes and remotely hosted internet programmes consistently increased knowledge and behaviours. Kiosk programmes showed evidence of modest knowledge and behaviour gains. Both programmes using mobile technology improved behaviours. Virtual-reality programmes consistently improved behaviours, but there were little gains in knowledge. No studies evaluated text-messaging programmes dedicated to injury prevention. CONCLUSIONS: There is much potential for computer-based programmes to be used for injury-prevention behaviour change. The reviewed studies provide evidence that computer-based communication is effective in conveying information and influencing how participants think about an injury topic and adopt safety behaviours.

Still too hot: examination of water temperature and water heater characteristics 24 years after manufacturers adopt voluntary temperature setting.

Although water heater manufacturers adopted a voluntary standard in the 1980s to preset thermostats on new water heaters to 120°F, tap water scald burns cause an estimated 1500 hospital admissions and 100 deaths per year in the United States. This study reports on water temperatures in 976 urban homes and identifies water heater and household characteristics associated with having safe temperatures. The temperature of the hot water, type and size of water heater, date of manufacture, and the setting of the temperature gauge were recorded. Demographic data, including number of people living in the home and home ownership, were also recorded. Hot water temperature was unsafe in 41% of homes. Homeowners were more likely to have safer hot water temperature (<120°F) than renters (63 vs 54%; P < .01). For 11% of gas water heaters, the water temperature was >130°F, although the gauge was set at less than 75% of its maximum setting. In a multivariate logistic regression, electric water heaters were more likely to have safe hot water temperatures than gas water heaters (odds ratio R=4.99; P < .01). Water heaters with more gallons per person in the household were more likely to be at or below the recommended 120°F. Our results suggest that hot water temperatures remain dangerously high for a substantial proportion of urban homes despite the adoption of voluntary standards to preset temperature settings by manufacturers. This research highlights the need for improved prevention strategies, such as installing thermostatic mixing valves, to ensure a safer temperature.