Citations

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor–mediated radiosensitization.

AbstractPurposeTo present a modified calibration method to reduce signal drift due to table sagging in Respiratory Gating for Scanner (RGSC) systems with a wall‐mounted camera.Materials and MethodsApproximately 70 kg of solid water phantoms were evenly distributed on the CT couch, mimicking the patient's weight. New calibration measurements were performed at 9 points at the combination of three lateral positions, the CT isocenter and ±10 cm laterally from the isocenter, and three longitudinal locations, the CT isocenter and ±30 cm or ±40 cm from the isocenter. The new calibration was tested in two hospitals.ResultsImplementing the new weighed calibration method at the extended distance yielded improved results during the DIBH scan, reducing the drift to within 1 from 3 mm. The extended calibration positions exhibited similarly reduced drift in both hospitals, reinforcing the method's robustness and its potential applicability across all centers.ConclusionThis proposed solution aims to minimize the systematic error in radiation delivery for patients undergoing motion management with wall‐mounted camera RGSC systems, especially in conjunction with a bariatric CT couchtop.

Background and Objectives: Acute small subcortical infarcts (SSI) result in high rates of early neurological deterioration (END) despite best medical management. Those with SSI-related END have worse functional outcomes after stroke leading to increased morbidity. Presently, it is unknown in a robust manner the incidence or risk factors for END within this demographic. The aim of this study was to perform a systematic review and meta-analysis to understand the incidence and risk factors of SSI-related END. Methods: We searched PubMed, Cochrane Library, and Google Scholar between January 1, 2000, and June 1, 2022, including both retrospective cross-sectional and prospective observational studies. The primary outcome was development of END based on publishing authors’ definition. Abstracted data included age, sex, cohort size, diagnoses of hypertension, hyperlipidemia, diabetes mellitus, study definition of END and SSI, and presence of branch atheromatous disease (BAD) and lesion diameter. Results: We identified 31 studies enrolling 6376 patients. Most studies were conducted in East Asia (27/31, 87%) and had a least some concern for risk of bias. Funnel plot illustrated a high level of publication bias favoring high incidence studies. END was commonly defined as ≥ 2 overall NIHSS change or ≥ 1 motor change within 3 to 7 days from admission (average: 5 days). A pooled proportion of END was 22% (95%CI 0.19 - 0.25, I2 = 91.2%, 31 studies). Meta-regression identified that female sex [risk ratio (RR) 1.23, 95%CI 1.09-1.39, I2=30.8%, 31 studies], diabetes mellitus (RR 1.16 95%CI 1.01-1.33, I2=38.4%, 30 studies), and BAD (RR 1.99 95%CI 1.61-2.46, I2=50.7%, 17 studies) as risk factors for END. Discussion: Our data identified primarily within an East Asian cohort that risk factors for SSI-related END include diabetes mellitus and branch atheromatous disease with a pooled prevalence of END occurring in 1 in 4 patients. Future studies are needed to understand treatment and preventative strategies for this patient population.

Abstract Extrachromosomal DNA (ecDNA) drives the evolution of cancer cells by conferring survival advantages over normal cells. However, the functional importance of ecDNA replication and maintenance is yet to be evaluated, and the molecular components that contributed to these processes remain largely unknown. Here, using CRISPR-C (circularization of genes and chromosomes by CRISPR) technology and synthetic circular DNA mimicking ecDNA identified in tumors, we generated ecDNA-positive (ecDNA+) cell models. Using these models, we identified the proteins involved in ecDNA replication and maintenance and found DNA damage response (DDR)-related pathways were significantly enriched. We further demonstrated that ecDNA replication led to increased DDR and genome instability and DDR was also essential for ecDNA maintenance, consistent with observations that ecDNA+ tumors exhibited higher DDR scores than ecDNA-negative (ecDNA–) tumors in patients. ATM, MDC1, and CHK2, but not ATR, were activated in ecDNA+ cells compared to ecDNA– cells. Moreover, ecDNA+ cells were more sensitive to ATM and CHK2 inhibition. We further found that type II topoisomerase TOP2B and DNA ligase III (LIG3) were critical regulators for ecDNA replication and maintenance and related DDR. In summary, our findings of the reciprocal interactions between ecDNA and DDR provide new insights into detection and therapy for ecDNA+ tumors.

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

AbstractThis article provides recommendations for implementing QSM for clinical brain research. It is a consensus of the International Society of Magnetic Resonance in Medicine, Electro‐Magnetic Tissue Properties Study Group. While QSM technical development continues to advance rapidly, the current QSM methods have been demonstrated to be repeatable and reproducible for generating quantitative tissue magnetic susceptibility maps in the brain. However, the many QSM approaches available have generated a need in the neuroimaging community for guidelines on implementation. This article outlines considerations and implementation recommendations for QSM data acquisition, processing, analysis, and publication. We recommend that data be acquired using a monopolar 3D multi‐echo gradient echo (GRE) sequence and that phase images be saved and exported in Digital Imaging and Communications in Medicine (DICOM) format and unwrapped using an exact unwrapping approach. Multi‐echo images should be combined before background field removal, and a brain mask created using a brain extraction tool with the incorporation of phase‐quality‐based masking. Background fields within the brain mask should be removed using a technique based on SHARP or PDF, and the optimization approach to dipole inversion should be employed with a sparsity‐based regularization. Susceptibility values should be measured relative to a specified reference, including the common reference region of the whole brain as a region of interest in the analysis. The minimum acquisition and processing details required when reporting QSM results are also provided. These recommendations should facilitate clinical QSM research and promote harmonized data acquisition, analysis, and reporting.

OBJECTIVE It is not clear whether there is an additive effect of social factors in keeping patients with cervical spondylotic myelopathy (CSM) from achieving both a minimum clinically important difference (MCID) in outcomes and satisfaction after surgery. The aim of this study was to explore the effect of multiple social factors on postoperative outcomes and satisfaction. METHODS This was a multiinstitutional, retrospective study of the prospective Quality Outcomes Database (QOD) CSM cohort, which included patients aged 18 years or older who were diagnosed with primary CSM and underwent operative management. Social factors included race (White vs non-White), education (high school or below vs above), employment (employed vs not), and insurance (private vs nonprivate). Patients were considered to have improved from surgery if the following criteria were met: 1) they reported a score of 1 or 2 on the North American Spine Society index, and 2) they met the MCID in patient-reported outcomes (i.e., visual analog scale [VAS] neck and arm pain, Neck Disability Index [NDI], and EuroQol-5D [EQ-5D]). RESULTS Of the 1141 patients included in the study, 205 (18.0%) had 0, 347 (30.4%) had 1, 334 (29.3%) had 2, and 255 (22.3%) had 3 social factors. The 24-month follow-up rate was > 80% for all patient-reported outcomes. After adjusting for all relevant covariates (p < 0.02), patients with 1 or more social factors were less likely to improve from surgery in all measured outcomes including VAS neck pain (OR 0.90, 95% CI 0.83–0.99) and arm pain (OR 0.88, 95% CI 0.80–0.96); NDI (OR 0.90, 95% CI 0.83–0.98); and EQ-5D (OR 0.90, 95% CI 0.83–0.97) (all p < 0.05) compared to those without any social factors. Patients with 2 social factors (outcomes: neck pain OR 0.86, arm pain OR 0.81, NDI OR 0.84, EQ-5D OR 0.81; all p < 0.05) or 3 social factors (outcomes: neck pain OR 0.84, arm pain OR 0.84, NDI OR 0.84, EQ-5D OR 0.84; all p < 0.05) were more likely to fare worse in all outcomes compared to those with only 1 social factor. CONCLUSIONS Compared to those without any social factors, patients who had at least 1 social factor were less likely to achieve MCID and feel satisfied after surgery. The effect of social factors is additive in that patients with a higher number of factors are less likely to improve compared to those with only 1 social factor.

OBJECTIVE The aim of this study was to identify predictors of the best 24-month improvements in patients undergoing surgery for cervical spondylotic myelopathy (CSM). For this purpose, the authors leveraged a large prospective cohort of surgically treated patients with CSM to identify factors predicting the best outcomes for disability, quality of life, and functional status following surgery. METHODS This was a retrospective analysis of prospectively collected data. The Quality Outcomes Database (QOD) CSM dataset (1141 patients) at 14 top enrolling sites was used. Baseline and surgical characteristics were compared for those reporting the top and bottom 20th percentile 24-month Neck Disability Index (NDI), EuroQol-5D (EQ-5D), and modified Japanese Orthopaedic Association (mJOA) change scores. A multivariable logistic model was constructed and included candidate variables reaching p ≤ 0.20 on univariate analyses. Least important variables were removed in a stepwise manner to determine the significant predictors of the best outcomes (top 20th percentile) for 24-month NDI, EQ-5D, and mJOA change. RESULTS A total of 948 (83.1%) patients with 24-month follow-up were included in this study. For NDI, 204 (17.9%) had the best NDI outcome and 200 (17.5%) had the worst NDI outcome. Factors predicting the best NDI outcomes included symptom duration less than 12 months (OR 1.5, 95% CI 1.1–1.9; p = 0.01); procedure other than posterior fusion (OR 1.5, 95% CI 1.03–2.1; p = 0.03); higher preoperative visual analog scale neck pain score (OR 1.2, 95% CI 1.1–1.3; p < 0.001); and higher baseline NDI (OR 1.06, 95% CI 1.05–1.07; p < 0.001). For EQ-5D, 163 (14.3%) had the best EQ-5D outcome and 169 (14.8%) had the worst EQ-5D outcome. Factors predicting the best EQ-5D outcomes included arm pain–only complaints (compared to neck pain) (OR 1.9, 95% CI 1.3–2.9; p = 0.002) and lower baseline EQ-5D (OR 167.7 per unit lower, 95% CI 85.0–339.4; p < 0.001). For mJOA, 222 (19.5%) had the best mJOA outcome and 238 (20.9%) had the worst mJOA outcome. Factors predicting the best mJOA outcomes included lower BMI (OR 1.03 per unit lower, 95% CI 1.004–1.05; p = 0.02; cutoff value of ≤ 29.5 kg/m 2 ); arm pain–only complaints (compared to neck pain) (OR 1.7, 95% CI 1.1–2.5; p = 0.02); and lower baseline mJOA (OR 1.6 per unit lower, 95% CI 1.5–1.7; p < 0.001). CONCLUSIONS Compared to the worst outcomes for EQ-5D, the best outcomes were associated with patients with arm pain–only complaints. For mJOA, lower BMI and arm pain–only complaints portended the best outcomes. For NDI, those with the best outcomes had shorter symptom durations, higher preoperative neck pain scores, and less often underwent posterior spinal fusions. Given the positive impact of shorter symptom duration on outcomes, these data suggest that early surgery may be beneficial for patients with CSM.

ABSTRACT In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.