Genome-wide Mapping of Topoisomerase Binding Sites Suggests Topoisomerase 3α (TOP3A) as a Reader of Transcription-Replication Conflicts (TRC).

Both transcription and replication can take place simultaneously on the same DNA template, potentially leading to transcription-replication conflicts (TRCs) and topological problems. Here we asked which topoisomerase(s) is/are the best candidate(s) for sensing TRC. Genome-wide topoisomerase binding sites were mapped in parallel for all the nuclear topoisomerases (TOP1, TOP2A, TOP2B, TOP3A and TOP3B). To increase the signal to noise ratio (SNR), we used ectopic expression of those topoisomerases in H293 cells followed by a modified CUT&Tag method. Although each topoisomerase showed distinct binding patterns, all topoisomerase binding signals positively correlated with gene transcription. TOP3A binding signals were suppressed by DNA replication inhibition. This was also observed but to a lesser extent for TOP2A and TOP2B. Hence, we propose the involvement of TOP3A in sensing both head-on TRCs (HO-TRCs) and co-directional TRCs (CD-TRCs). In which case, the TOP3A signals appear concentrated within the promoters and first 20 kb regions of the 5' -end of genes, suggesting the prevalence of TRCs and the recruitment of TOP3A in the 5'-regions of transcribed and replicated genes.

Noncovalent Interactions-Driven Self-Assembly of Polyanionic Additive for Long Anti-Calendar Aging and High-Rate Zinc Metal Batteries.

Zinc anodes of zinc metal batteries suffer from unsatisfactory plating/striping reversibility due to interfacial parasitic reactions and poor Zn2+ mass transfer kinetics. Herein, methoxy polyethylene glycol-phosphate (mPEG-P) is introduced as an electrolyte additive to achieve long anti-calendar aging and high-rate capabilities. The polyanionic of mPEG-P self-assembles via noncovalent-interactions on electrode surface to form polyether-based cation channels and in situ organic-inorganic hybrid solid electrolyte interface layer, which ensure rapid Zn2+ mass transfer and suppresses interfacial parasitic reactions, realizing outstanding cycling/calendar aging stability. As a result, the Zn//Zn symmetric cells with mPEG-P present long lifespans over 9000 and 2500 cycles at ultrahigh current densities of 120 and 200 mA cm-2, respectively. Besides, the coulombic efficiency (CE) of the Zn//Cu cell with mPEG-P additive (88.21%) is much higher than that of the cell (36.4%) at the initial cycle after the 15-day calendar aging treatment, presenting excellent anti-static corrosion performance. Furthermore, after 20-day aging, the Zn//MnO2 cell exhibits a superior capacity retention of 89% compared with that of the cell without mPEG-P (28%) after 150 cycles. This study provides a promising avenue for boosting the development of high efficiency and durable metallic zinc based stationary energy storage system.

Towards wearable and portable spine motion analysis through dynamic optimization of smartphone videos and IMU data.

BACKGROUND: Monitoring spine kinematics is crucial for applications like disease evaluation and ergonomics analysis. However, the small scale of vertebrae and the number of degrees of freedom present significant challenges for noninvasive and convenient spine kinematics estimation. METHODS: This study developed a dynamic optimization framework for wearable spine motion tracking at the intervertebral joint level by integrating smartphone videos and Inertia Measurement Units (IMUs) with dynamic constraints from a thoracolumbar spine model. Validation involved motion data from 10 healthy males performing static standing, dynamic upright trunk rotations, and gait. This data included rotations of ten IMUs on vertebrae and virtual landmarks from three smartphone videos preprocessed by OpenCap, an application leveraging computer vision for pose estimation. The kinematic measures derived from the optimized solution were compared against simultaneously collected infrared optical marker-based measurements and in vivo literature data. Solutions only based on IMUs or videos were also compared for accuracy evaluation. RESULTS: The proposed optimization approach closely matched the reference data in the intervertebral or segmental rotation range, demonstrating minimal angular differences across all motions and the highest correlation in 3D rotations (maximal Pearson and intraclass correlation coefficients of 0.92 and 0.94, respectively). Time-series changes of joint angles also aligned well with the optical-marker reference. CONCLUSION: Dynamic optimization of the spine simulation that integrates IMUs and computer vision outperforms the single-modality method. SIGNIFICANCE: This markerless 3D spine motion capture method holds potential for spinal health assessment in large cohorts in real-world settings without dedicated laboratories.

Phoenix Sepsis Score and Risk of Attributable Mortality in Children With Cancer.

This prognostic study analyzes the accuracy of the Phoenix Sepsis Score for the classification of attributable mortality risk in children with cancer presenting to the intensive care.

Harnessing Ion-Dipole Interactions for Water-Lean Solvation Chemistry: Achieving High-Stability Zn Anodes in Aqueous Zinc-Ion Batteries.

The reversibility and stability of aqueous zinc-ion batteries (AZIBs) are largely limited by water-induced interfacial parasitic reactions. Here, dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (DP) is introduced to tailor primary solvation sheath and inner-Helmholtz configurations for robust zinc anode. Informed by theoretical guidance on solvation process, DP with high permanent dipole moments can effectively substitute the coordination of H2O with charge carriers through relatively strong ion-dipolar interactions, resulting in a water-lean environment of solvated Zn2+. Thus, interfacial side reactions can be suppressed through a shielding effect. Meanwhile, lone-pair electrons of oxygen and fluorinated features of DP also reinforce the interfacial affinity of metallic zinc, associated with exclusion of neighboring water to facilitate reversible zinc planarized deposition. Thus, these merits endow the Zn anode with a high-stability performance exceeds 3800 hours at 0.5 mA cm-2 and 0.5 mAh cm-2 for Zn||Zn batteries and a high average Coulombic efficiency of 99.8 % at 4 mA cm-2 and 1 mAh cm-2 for Zn||Cu batteries. Benefiting from the stable zinc anode, the Zn||NH4V4O10 cell maintains 80.3 % of initial discharge capacity after 3000 cycles at 5 A g-1 and exhibits a high retention rate of 99.4 % against to the initial capacity during the self-discharge characterizations.

Impact of Clinical Trial Design on Recruitment of Racial and Ethnic Minorities.

Knowledge related to how oncology treatment trial design influences enrollment of racial and ethnic minorities is limited. Rigorous identification of clinical trial design parameters that associate favorably with minority accrual provides educational opportunities for individuals interested in designing more representative treatment trials. We identified oncology trials with a minimum of 10 patients at an NCI-Designated Comprehensive Cancer Center from 2010 to 2021. We defined a study endpoint of racial and ethnic minority accrual greater than zero. Multivariable logistic regression was used to determine whether co-variables predicted our study endpoint. P-values of less than 0.05 were considered significant. A total of 352 cancer trials met eligibility criteria. These studies enrolled a total of 7981 patients with a total of 926 racial and ethnic minorities leading to a median enrollment of 10%. Trials open in community sites (yes versus no) were more likely to have a minority patient (OR, 2.21; 95% CI, 1.02-4.96) as well as pilot/phase I studies compared to phase II/III (OR, 3.19; 95% CI, 1.34-8.26). Trials incorporating immunotherapy (yes versus no) were less likely to have a minority patient (OR, 0.47; 95% CI, 0.23-0.94). Trials open in community sites as well as early phase treatment studies were more likely to accrue minority patients. However, studies including immunotherapy were less likely to accrue racial and ethnic minorities. Knowledge gained from our analysis may help individuals design oncology treatment trials that are representative of more diverse populations.

Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis.

BACKGROUND AND OBJECTIVE: The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC. METHODS: Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation. KEY FINDINGS AND LIMITATIONS: Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42). CONCLUSIONS AND CLINICAL IMPLICATIONS: There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.

The promotion of the atrazine degradation mechanism by humic acid in a soil microbial electrochemical system.

The enhancing effects of anodes on the degradation of the organochlorine pesticide atrazine (ATR) in soil within microbial electrochemical systems (MES) have been extensively researched. However, the impact and underlying mechanisms of soil microbial electrochemical systems (MES) on ATR degradation, particularly under conditions involving the addition of humic acids (HAs), remain elusive. In this investigation, a soil MES supplemented with humic acids (HAs) was established to assess the promotional effects and mechanisms of HAs on ATR degradation, utilizing EEM-PARAFAC and SEM analyses. Results revealed that the maximum power density of the MES in soil increased by 150%, and the degradation efficiency of ATR improved by over 50% following the addition of HAs. Furthermore, HAs were found to facilitate efficient ATR degradation in the far-anode region by mediating extracellular electron transfer. The components identified as critical in promoting ATR degradation were Like-Protein and Like-Humic acid substances. Analysis of the microbial community structure indicated that the addition of HAs favored the evolution of the soil MES microbial community and the enrichment of electroactive microorganisms. In the ATR degradation process, the swift accumulation of Hydrocarbyl ATR (HYA) was identified as the primary cause for the rapid degradation of ATR in electron-rich conditions. Essentially, HA facilitates the reduction of ATR to HYA through mediated bonded electron transfer, thereby markedly enhancing the efficiency of ATR degradation.

Invasive Nodal Staging via Endobronchial Ultrasound and Outcome in Patients Treated with Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer - Results from a Single Institution Study.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an effective treatment for medically inoperable early-stage non-small cell lung cancer (NSCLC). The prognostic value of invasive nodal staging (INS) for patients undergoing SRBT has not been studied extensively. Herein, we report the impact of INS in addition to 18F-FDG-PET on treatment outcome for patients with NSCLC undergoing SBRT. MATERIALS AND METHODS: Patients with stage I/ II NSCLC who underwent SBRT were included with IRB approval. Clinical, dosimetric, and radiological data were obtained. Overall survival (OS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), and distant recurrence free survival (DRFS) were analyzed using Kaplan Meyer method. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to assess the relationship between the variables and the outcomes. RESULTS: A total of 376 patients were included in the analysis. Median follow up was 43 months (IQ 32.6-45.8). Median OS, LRFS, RRFS, DRFS were 40, 32, 32, 33 months, respectively. The 5-year local, regional, and distant failure rates were 13.4%, 23.5% and 25.3%, respectively. The 1-year, 3-year and 5-year OS were 83.8%, 55.6%, and 36.3%, respectively. On MVA, INS was not a predictor of either improved overall or any recurrence free survival endpoints while larger tumor size, age, and adjusted Charleston co-morbidity index (aCCI) were significant for inferior LRFS, RRFS, and DRFS. CONCLUSION: Invasive nodal staging did not improve overall or recurrence free survival among patients with early-stage NSCLC treated with SBRT whereas older age, aCCI, and larger tumor size were significant predictors of LRFS, RRFS, and DRFS.

Evaluation of Continuous Infusion Vancomycin in a Pediatric Hematology/Oncology Population.

BACKGROUND: Continuous infusion vancomycin (CIV) may benefit children who are unable to achieve therapeutic concentrations with intermittent vancomycin dosing and may facilitate outpatient administration by alleviating the burden of frequent dosing intervals. Previous studies have used variable dosing regimens and steady-state concentration goals. The purpose of this study was to evaluate the total daily dose (TDD) of CIV required to achieve therapeutic steady-state concentrations of 15-25 µg/mL in pediatric hematology/oncology patients. METHODS: A single-center retrospective study was performed for patients treated with CIV from January 2017 to June 2019. The primary outcome was the TDD required to achieve therapeutic steady-state concentrations on CIV. Secondary outcomes included time to reach therapeutic steady-state concentrations, CIV indications and adverse events associated with CIV. RESULTS: Data were collected for 71 courses of CIV in 60 patients. Median patient age was 4 years (range: 0.4-20 years). The median TDD required to achieve initial therapeutic concentrations was 50.3 mg/kg/d (interquartile range: 38.8-59.2) and was further divided into age-based cohorts. TDD in mg/kg was significantly lower in the older cohort ( P < 0.001), but there was no statistically significant difference between age-based cohorts with TDD in mg/m 2 ( P = 0.97). Median time to achieve first therapeutic concentration was 19.3 hours (range: 8.6-72.3 hours). The most common indication for CIV was ease of outpatient administration (69.0%). Acute kidney injury incidence was minimal (4.2%). CONCLUSIONS: CIV is associated with rapid attainment of target concentrations in pediatric hematology/oncology patients and is safe and well tolerated.

Effect of Concomitant Medications on Treatment Response and Survival in De Novo Metastatic Prostate Cancer: Secondary Analysis of the LATITUDE Study.

PURPOSE: It is unclear whether exposure to commonly prescribed medications influences survival and treatment response in patients with de novo high-risk metastatic prostate cancer (mPCa) treated with androgen receptor pathway inhibitors (ARPIs). METHODS: We performed a secondary analysis of the LATITUDE trial to determine whether receipt of concomitant medications influenced the effect of abiraterone acetate and prednisone, in addition to androgen deprivation therapy (ADT), on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with de novo mPCa. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors (PPIs), cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors). To account for multiple testing, a two-sided p < 0.0024 was set as the threshold for statistical significance. RESULTS: Overall, 1135 patients were eligible. There was some evidence of a differential treatment effect from abiraterone among patients who received concomitant NSAIDs (hazard ratio [HR] for OS: 0.54; 95% CI: 0.42-0.70) versus those who did not (HR: 0.74; 95% CI: 0.60-0.91), though this did not reach significance (interaction p = 0.05). A similar non-significant finding of heterogeneity of effect from abiraterone was noted among patients who received concomitant aspirin (HR for OS: 0.93 [0.63-1.36]) versus those who did not (HR: 0.61 [0.51-0.73]) (interaction p = 0.04). Receipt of NSAIDs was independently associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p < 0.001) and higher relative incidence of PCSM (sHR: 1.47 [1.21-1.78]; p < 0.001). CONCLUSIONS: This exploratory analysis did not find statistically significant evidence of differences in treatment effects from ADT plus abiraterone in de novo high-risk mPCa based on the receipt of concurrent medications. The receipt of NSAIDs was independently associated with increased PCSM and inferior OS.

Formations of C6H from reactions C3 + C3H2 and C3H + C3H and of C8H from reactions C4 + C4H2 and C4H + C4H.

We interrogated C6H and C8H produced separately from the reactions C3 + C3H2/C3H + C3H/C3H2 + C3 → C6H + H and C4 + C4H2/C4H + C4H/C4H2 + C4 → C8H + H using product translational and photoionization spectroscopy. Individual contributions of the three reactions to the product C6H or C8H were evaluated with reactant concentrations. Translational-energy distributions, angular distributions, and photoionization efficiency curves of products C6H and C8H were unraveled. The product C6H (C8H) was recognized as the most stable linear isomer by comparing its photoionization efficiency curve with that of l-C6H (l-C8H), produced exclusively from the reaction C2 + C4H2 → l-C6H + H (C2 + C6H2 → l-C8H + H). The ionization threshold after deconvolution was determined to be 9.3 ± 0.1 eV for l-C6H and 8.9 ± 0.1 eV for l-C8H, which is in good agreement with theoretical values. Quantum-chemical calculations indicate that the reactions of C3 + C3H2 and C3H + C3H (C4 + C4H2 and C4H + C4H) incur no energy barriers that lie above the corresponding reactant and the most stable product l-C6H (l-C8H) with H on the lower-lying potential-energy surfaces. The theoretical calculation is in accord with the experimental observation. This work implies that the reactions of C3 + C3H2/C3H + C3H and C4 + C4H2/C4H + C4H need to be taken into account for the formation of interstellar C6H and C8H, respectively.

Study on Formation of Interstellar C7H from Reactions C4 + C3H2 and C4H + C3H.

We interrogated C7H produced from reactions C4 + C3H2/C4H + C3H → C7H + H using both translational and photoionization spectroscopy. Reactants C3H, C3H2, C4, and C4H were synthesized in two crossed beams of 1% C2H2/He ignited by pulsed high-voltage discharge. The individual contributions of reactions C4 + C3H2 and C4H + C3H to product C7H were evaluated as 17:83 from reactant concentrations in both molecular beams. The translational energy distribution, the angular distribution, and the photoionization efficiency curve of product C7H were unraveled. C7H was identified as the most stable linear isomer by its photoionization efficiency curve that features two ionization thresholds corresponding to separate transitions to singlet and triplet states of l-C7H+. The quantum-chemical calculations indicate that the associations of C4 with C3H2 and C4H with C3H incur no entrance barriers, and the most favorable exit channel leads to product l-C7H + H. It is the first time demonstrating that C7H is producible from reactions 1,3C4 + 1C3H2 and 2C4H + 2C3H on the lowest-lying singlet and triplet potential energy surfaces of 1,3C7H2. This work implies that the reactions of C4 + C3H2 and C4H + C3H might have contributions to interstellar C7H to some extent as compared with the C + C6H2 reaction commonly adopted in an astrochemical model.

Effect of Pelvic External Beam Radiation Therapy on Bone Mineral Density: A Secondary Analysis of a Phase 3 Randomized Controlled Trial.

PURPOSE: Pelvic radiation therapy may lead to decreased bone mineral density (BMD) and increased risk of fracture that could be of particular concern in patients with prostate cancer who also receive androgen deprivation therapy (ADT). We performed an exploratory analysis of a randomized, double-masked, placebo-controlled trial to determine whether exposure to prior pelvic external beam radiation therapy (XRT) affects BMD and risk of fracture in patients with prostate cancer treated with ADT. METHODS AND MATERIALS: Patients with nonmetastatic prostate cancer aged ≥70 years or <70 years with low BMD (T-score < -1) or osteoporotic fracture who had been receiving ADT for ≥12 months were randomly assigned to receive densoumab or placebo every 6 months for 3 years. BMD was measured at baseline and at months 1, 3, 6, 12, 24, and 36. We applied multivariable linear mixed-effects models with an interaction term between the treatment arm and exposure to prior pelvic XRT to evaluate differential XRT effect on percent BMD change between the 2 treatment arms. RESULTS: Among 1407 eligible patients, 31% (n = 447) received prior pelvic XRT. There was no significant difference in any clinical fractures among patients with (5.8%, 26 of 447) or without (5.2%, 50 of 960) prior pelvic XRT (P = .42). Prior pelvic XRT was associated with a significant (0.54%) improvement in BMD (95% CI, 0.05-1.02) in the placebo group and a nonsignificant (0.04%) decline in BMD (95% CI, -0.47 to -0.35) in the denosumab group (interaction P = .007). There was no significant difference in pelvic XRT effect on percent BMD change in the lumbar spine (P = .65) or total hip (P = .39) between the 2 treatment groups. CONCLUSIONS: We did not find sufficient evidence to suggest any detrimental effect of pelvic XRT on the treatment effect from denosumab on percent BMD change, with only an approximately 5% incidence of clinical fractures.

Insurance Denial of Care for Randomized Controlled Trial-Eligible Patients: Incidence and Success Rate of Peer-To-Peer Authorization in Allowing Patients to Remain Trial-Eligible.

INTRODUCTION: Insurance denials for clinical trials serve as a pertinent barrier for patients to remain trial-eligible, thus hindering the development of therapies and the overall advancement of health care. We present results from an ongoing oncology randomized clinical trial regarding insurance denials and peer-to-peer authorization (P2PA) success rate in allowing patients to remain trial-eligible. METHODS: The ongoing Spine Patient Optimal Radiosurgery Treatment for Symptomatic Metastatic Neoplasms Phase II trial randomizes spine cancer patients to treatment with spine radiosurgery/stereotactic body radiation therapy (SBRT) versus conventional external beam radiation therapy (EBRT). Trial-eligible patients during the first 3 months of enrollment are examined to determine whether the option of SBRT was denied by their insurance. Advocacy for overcoming SBRT denial in P2PA centered on SBRT being recommended as a preferred treatment modality in the National Comprehensive Cancer Network guidelines, and the recent level I evidence demonstrating the advantages of SBRT over EBRT for symptomatic spine cancer. RESULTS: Of 15 trial-eligible patients, 3 (20%) experienced insurance denials for SBRT. P2PA resulted in the reversal of denials in all 3 patients, allowing each to remain trial-eligible for randomization between SBRT and cEBRT. CONCLUSIONS: Despite a clinical oncologic treatment modality for which recent Level 1 evidence is available, the insurance denial rate was 20%. A vigilant P2PA strategy focusing on highlighting National Comprehensive Cancer Network guidelines and the supporting Level 1 evidence resulted in a very high rate of reversing initial denial.

Longitudinal clinical data improve survival prediction after hematopoietic cell transplantation using machine learning.

ABSTRACT: Serial prognostic evaluation after allogeneic hematopoietic cell transplantation (allo-HCT) might help identify patients at high risk of lethal organ dysfunction. Current prediction algorithms based on models that do not incorporate changes to patients' clinical condition after allo-HCT have limited predictive ability. We developed and validated a robust risk-prediction algorithm to predict short- and long-term survival after allo-HCT in pediatric patients that includes baseline biological variables and changes in the patients' clinical status after allo-HCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training data set (70% of the cohort), internally validated (remaining 30% of the cohort) and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before allo-HCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1 year, and 2 years after allo-HCT. Naïve-Bayes machine learning models incorporating longitudinal data were significantly better than models constructed from baseline variables alone at predicting whether patients would be alive or deceased at the given time points. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing allo-HCT.

RAD54L2-mediated DNA damage avoidance pathway specifically preserves genome integrity in response to topoisomerase 2 poisons.

Type II topoisomerases (TOP2) form transient TOP2 cleavage complexes (TOP2ccs) during their catalytic cycle to relieve topological stress. TOP2ccs are covalently linked TOP2-DNA intermediates that are reversible but can be trapped by TOP2 poisons. Trapped TOP2ccs block transactions on DNA and generate genotoxic stress, which are the mechanisms of action of TOP2 poisons. How cells avoid TOP2cc accumulation remains largely unknown. In this study, we uncovered RAD54 like 2 (RAD54L2) as a key factor that mediates a TOP2-specific DNA damage avoidance pathway. RAD54L2 deficiency conferred unique sensitivity to treatment with TOP2 poisons. RAD54L2 interacted with TOP2A/TOP2B and ZATT/ZNF451 and promoted the turnover of TOP2 from DNA with or without TOP2 poisons. Additionally, inhibition of proteasome activity enhanced the chromatin binding of RAD54L2, which in turn led to the removal of TOP2 from chromatin. In conclusion, we propose that RAD54L2-mediated TOP2 turnover is critically important for the avoidance of potential TOP2-linked DNA damage under physiological conditions and in response to TOP2 poisons.

Prediction of attributable mortality in pediatric patients with cancer admitted to the intensive care unit for suspected infection: A comprehensive evaluation of risk scores.

OBJECTIVE: To evaluate the performance of existing sepsis scores for prediction of adverse outcomes in children with cancer admitted to the ICU with suspected sepsis. DESIGN: Retrospective chart review using data available at 1, 6, 12, and 24 h after ICU admission to calculate the Pediatric Risk of Mortality 3 (PRISM-3), Pediatric Sequential Organ Failure Assessment (pSOFA), Paediatric Logistic Organ Dysfunction 2 (PELOD-2), and Quick Pediatric Sequential Organ Failure Assessment (qSOFA) scores. Area under the receiver operator characteristic curve (AUROC) was used to evaluate performance for prediction of attributable mortality. Sensitivity analyses included recalculation of scores using worst preceding values for each variable, excluding hematologic parameters, and prediction of alternative outcomes. SETTING: St. Jude Children's Research Hospital, a pediatric comprehensive cancer center in the USA. PATIENTS: Pediatric patients (<25 years of age) receiving conventional therapy for cancer admitted to the ICU with suspected sepsis between 2013 and 2019. RESULTS: Of 207 included episodes of suspected sepsis, attributable mortality was 16 (7.7%) and all evaluated sepsis scores performed poorly (maximal AUROC of 0.73 for qSOFA at 1 and 24 h). Sensitivity analyses did not identify an alternative approach that significantly improved prediction. CONCLUSIONS: Currently available sepsis scores perform poorly for prediction of attributable mortality in children with cancer who present to ICU with suspected sepsis. More research is needed to identify reliable predictors of adverse outcomes in this population.