Analysis of Oncology and Radiation Therapy Representation on the National Board of Medical Examiners Official Practice Material for the United States National Standardized Medical Board Examinations.

Radiation therapy (RT) is a critical component of multidisciplinary cancer care, but has inconsistent curricular exposure. We characterize the radiation oncology (RO) content on the standardized undergraduate medical examinations by comparing its context and prevalence with other domains in oncology. National Board of Medical Examiners (NBME) self-assessments and sample questions for the United States Medical Licensing Exam (USMLE) Steps 1-3 and NBME clinical science shelf examinations were accessed (n = 3878). Questions were inductively analyzed for content pertaining to oncology and treatment modalities of RT, systemic therapy (ST), and surgical intervention (SI). Questions were coded using USMLE Physician Tasks/Competencies and thematic analysis. Descriptive statistics and analyses using the Kruskal-Wallis test are reported. A total of 337 questions (8.6%) within the USMLE and shelf exams included oncology content, with 101 questions (2.6%) referencing at least one cancer treatment modality (n = 35 RT, 45 ST, 57 SI). Treatment questions were more common on USMLE Step 2 CK (n = 35/101, 32%) compared to Step 1 (n = 23/101, 23%) and Step 3 (n = 8/101, 8%) (p < 0.001). RT was significantly less likely to be the correct answer (2/35, 6%) compared to ST (4/45, 9%) and SI (18/57, 32%) (p = 0.003). Therapeutic oncology questions are uncommon on the examination material, with an under-representation of radiation-related content, and contextual bias favoring surgical approaches. We advocate for greater RO involvement in the content creation of such examinations to help trainees better understand multidisciplinary cancer care.

Factors Associated With Open Access Publishing Costs in Oncology Journals: Cross-sectional Observational Study.

BACKGROUND: Open access (OA) publishing represents an exciting opportunity to facilitate the dissemination of scientific information to global audiences. However, OA publishing is often associated with significant article processing charges (APCs) for authors, which may thus serve as a barrier to publication. OBJECTIVE: In this observational cohort study, we aimed to characterize the landscape of OA publishing in oncology and, further, identify characteristics of oncology journals that are predictive of APCs. METHODS: We identified oncology journals using the SCImago Journal & Country Rank database. All journals with an OA publication option and APC data openly available were included. We searched journal websites and tabulated journal characteristics, including APC amount (in US dollars), OA model (hybrid vs full), 2-year impact factor (IF), H-index, number of citable documents, modality/treatment specific (if applicable), and continent of origin. All APCs were converted to US-dollar equivalents for final analyses. Selecting variables with significant associations in the univariable analysis, we generated a multiple regression model to identify journal characteristics independently associated with OA APC amount. An audit of a random 10% sample of the data was independently performed by 2 authors to ensure data accuracy, precision, and reproducibility. RESULTS: Of 367 oncology journals screened, 251 met the final inclusion criteria. The median APC was US $2957 (IQR 1958-3450). The majority of journals (n=156, 62%) adopted the hybrid OA publication model and were based in Europe (n=119, 47%) or North America (n=87, 35%). The median (IQR) APC for all journals was US $2957 (1958-3540). Twenty-five (10%) journals had APCs greater than US $4000. There were 10 (4%) journals that offered OA publication with no publication charge. Univariable testing showed that journals with a greater number of citable documents (P<.001), higher 2-year IF (P<.001), higher H-index (P<.001), and those using the hybrid OA model (P<.001), or originating in Europe or North America (P<.001) tended to have higher APCs. In our multivariable model, the number of citable documents (ß=US $367, SD US $133; P=.006), 2-year IF (US $1144, SD US $177; P<.001), hybrid OA publishing model (US $991, SD US $189; P<.001), and North American origin (US $838, SD US $186; P<.001) persisted as significant predictors of processing charges. CONCLUSIONS: OA publication costs are greater in oncology journals that publish more citable articles, use the hybrid OA model, have a higher IF, and are based in North America or Europe. These findings may inform targeted action to help the oncology community fully appreciate the benefits of open science.

Impact factor and citation metrics in phase III cancer trials.

PURPOSE: Journal impact factor (IF) is often used to measure research quality and importance. We assessed trial factors associated with the publication of cancer trials in journals with higher IF and publications receiving higher citations. MATERIALS AND METHODS: Cancer-specific phase III RCTs were screened through https://clinicaltrials.gov. We identified trials with published primary endpoints, along with their corresponding journal IF and relative citation ratio (RCR). RESULTS: Seven-hundred ninety manuscripts were included in our study. Trials that met their primary endpoint were more commonly published in journals with higher IF (Median IF: positive trials 35.4 vs. negative trials 26.3, P < 0.001). Furthermore, trials that led to subsequent FDA drug approvals were also published in journals with higher IF (Median IF: 59.1 vs. 26.3 in trials not leading to FDA approvals, P < 0.001). When analyzing RCR, trial positivity (meeting primary endpoint) was not associated with increased citations on multivariable analysis (P = 0.56). Lastly, publications of trials leading to FDA approvals (P < 0.001), and publications of trials in journals with higher IF (P < 0.001) were associated with increased RCR. CONCLUSIONS: Positive trials are commonly published in journals with high IF, but do not necessarily lead to increased citations. Moreover, trials published in journals with higher IF are more likely to receive increased citations.

New insights into abasic site repair and tolerance.

Thousands of apurinic/apyrimidinic (AP or abasic) sites form in each cell, each day. This simple DNA lesion can have profound consequences to cellular function, genome stability, and disease. As potent blocks to polymerases, they interfere with the reading and copying of the genome. Since they provide no coding information, they are potent sources of mutation. Due to their reactive chemistry, they are intermediates in the formation of lesions that are more challenging to repair including double-strand breaks, interstrand crosslinks, and DNA protein crosslinks. Given their prevalence and deleterious consequences, cells have multiple mechanisms of repairing and tolerating these lesions. While base excision repair of abasic sites in double-strand DNA has been studied for decades, new interest in abasic site processing has come from more recent insights into how they are processed in single-strand DNA. In this review, we discuss the source of abasic sites, their biological consequences, tolerance mechanisms, and how they are repaired in double and single-stranded DNA.

The Bromodomain Protein 4 Contributes to the Regulation of Alternative Splicing.

The bromodomain protein 4 (BRD4) is an atypical kinase and histone acetyl transferase (HAT) that binds to acetylated histones and contributes to chromatin remodeling and early transcriptional elongation. During transcription, BRD4 travels with the elongation complex. Since most alternative splicing events take place co-transcriptionally, we asked if BRD4 plays a role in regulating alternative splicing. We report that distinct patterns of alternative splicing are associated with a conditional deletion of BRD4 during thymocyte differentiation in vivo. Similarly, the depletion of BRD4 in T cell acute lymphoblastic leukemia (T-ALL) cells alters patterns of splicing. Most alternatively spliced events affected by BRD4 are exon skipping. Importantly, BRD4 interacts with components of the splicing machinery, as assessed by both immunoprecipitation (IP) and proximity ligation assays (PLAs), and co-localizes on chromatin with the splicing regulator, FUS. We propose that BRD4 contributes to patterns of alternative splicing through its interaction with the splicing machinery during transcription elongation.

Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link.

Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. 5-hydroxymethylcytosine binding, embryonic stem cell-specific protein (HMCES) recognizes and processes these lesions in the context of single-stranded DNA (ssDNA). A HMCES DNA-protein cross-link (DPC) intermediate is thought to shield the AP site from endonucleases and error-prone polymerases. The highly evolutionarily conserved SOS-response associated peptidase (SRAP) domain of HMCES and its Escherichia coli ortholog YedK mediate lesion recognition. Here we uncover the basis of AP site protection by SRAP domains from a crystal structure of the YedK DPC. YedK forms a stable thiazolidine linkage between a ring-opened AP site and the α-amino and sulfhydryl substituents of its amino-terminal cysteine residue. The thiazolidine linkage explains the remarkable stability of the HMCES DPC, its resistance to strand cleavage and the proteolysis requirement for resolution. Furthermore, its structure reveals that HMCES has specificity for AP sites in ssDNA at junctions found when replicative polymerases encounter the AP lesion.

HMCES Maintains Genome Integrity by Shielding Abasic Sites in Single-Strand DNA.

Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation. Acting as a suicide enzyme, HMCES prevents translesion DNA synthesis and the action of endonucleases that would otherwise generate mutations and double-strand breaks. HMCES is evolutionarily conserved in all domains of life, and its biochemical properties are shared with its E. coli ortholog. Thus, HMCES is an ancient DNA lesion recognition protein that preserves genome integrity by promoting error-free repair of abasic sites in single-stranded DNA.

Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction.

Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 ≤ induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments.

A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.

The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic.