Network Rewiring of Homologous Recombination Enzymes during Mitotic Proliferation and Meiosis.

Homologous recombination (HR) is essential for high-fidelity DNA repair during mitotic proliferation and meiosis. Yet, context-specific modifications must tailor the recombination machinery to avoid (mitosis) or enforce (meiosis) the formation of reciprocal exchanges-crossovers-between recombining chromosomes. To obtain molecular insight into how crossover control is achieved, we affinity purified 7 DNA-processing enzymes that channel HR intermediates into crossovers or noncrossovers from vegetative cells or cells undergoing meiosis. Using mass spectrometry, we provide a global characterization of their composition and reveal mitosis- and meiosis-specific modules in the interaction networks. Functional analyses of meiosis-specific interactors of MutLγ-Exo1 identified Rtk1, Caf120, and Chd1 as regulators of crossing-over. Chd1, which transiently associates with Exo1 at the prophase-to-metaphase I transition, enables the formation of MutLγ-dependent crossovers through its conserved ability to bind and displace nucleosomes. Thus, rewiring of the HR network, coupled to chromatin remodeling, promotes context-specific control of the recombination outcome.

Multidimensional regularity processing in music: an examination using redundant signals effect.

Music is based on various regularities, ranging from the repetition of physical sounds to theoretically organized harmony and counterpoint. How are multidimensional regularities processed when we listen to music? The present study focuses on the redundant signals effect (RSE) as a novel approach to untangling the relationship between these regularities in music. The RSE refers to the occurrence of a shorter reaction time (RT) when two or three signals are presented simultaneously than when only one of these signals is presented, and provides evidence that these signals are processed concurrently. In two experiments, chords that deviated from tonal (harmonic) and acoustic (intensity and timbre) regularities were presented occasionally in the final position of short chord sequences. The participants were asked to detect all deviant chords while withholding their responses to non-deviant chords (i.e., the Go/NoGo task). RSEs were observed in all double- and triple-deviant combinations, reflecting processing of multidimensional regularities. Further analyses suggested evidence of coactivation by separate perceptual modules in the combination of tonal and acoustic deviants, but not in the combination of two acoustic deviants. These results imply that tonal and acoustic regularities are different enough to be processed as two discrete pieces of information. Examining the underlying process of RSE may elucidate the relationship between multidimensional regularity processing in music.

Multifaceted regulation of the sumoylation of the Sgs1 DNA helicase.

Homologous recombination repairs DNA breaks and sequence gaps via the production of joint DNA intermediates such as Holliday junctions. Dissolving Holliday junctions into linear DNA repair products requires the activity of the Sgs1 helicase in yeast and of its homologs in other organisms. Recent studies suggest that the functions of these conserved helicases are regulated by sumoylation; however, the mechanisms that promote their sumoylation are not well understood. Here, we employed in vitro sumoylation systems and cellular assays to determine the roles of DNA and the scaffold protein Esc2 in Sgs1 sumoylation. We show that DNA binding enhances Sgs1 sumoylation in vitro. In addition, we demonstrate the Esc2's midregion (MR) with DNA-binding activity is required for Sgs1 sumoylation. Unexpectedly, we found that the sumoylation-promoting effect of Esc2-MR is DNA independent, suggesting a second function for this domain. In agreement with our biochemical data, we found the Esc2-MR domain, like its SUMO E2-binding C-terminal domain characterized in previous studies, is required for proficient sumoylation of Sgs1 and its cofactors, Top3 and Rmi1, in cells. Taken together, these findings provide evidence that while DNA binding enhances Sgs1 sumoylation, Esc2-based stimulation of this modification is mediated by two distinct domains.

A combined bioinformatics and experimental approach identifies RMI2 as a Wnt/ß-catenin signaling target gene related to hepatocellular carcinoma.

BACKGROUND: The Wnt/ß-catenin signaling pathway plays an important role in embryogenesis and tumorigenesis. In human cancer, abnormal activity of Wnt/ß-catenin signaling pathway induces overexpressed of downstream genes, and initiate oncogene. There are several target genes known to be key players in tumorigenesis, such as c-myc, cyclin D1, MMPs or survivin. Therefore, identifying the target genes of Wnt/ß-catenin signaling pathway is important to understanding Wnt/ß-catenin-mediated carcinogenesis. In this study, we developed a combined bioinformatics and experimental approach to find potential target genes. METHODS: Luciferase reporter assay was used to analyze the promoter activity of RMI2. WST1 cell proliferation assays and transwell assays were performed to determine the proliferation and migration capacities of RMI2 overexpressing or knockdown stable hepatic cells. Finally, xenograft experiments were performed to measure the tumor formation capacity in vivo. RESULTS: The results showed that RMI2 mRNA was upregulated after LiCl treatment and Wnt3a-conditioned medium in a culture of SK-hep-1 cell lines. A chromatin immunoprecipitation (ChIP) assay showed that the ß-catenin/T cell-specific factor (TCF) complex binds to the putative TCF binding site of the RMI2 promoter. We then found a TCF binding site at - 333/- 326 of the RMI2 promoter, which is crucial for ß-catenin responsiveness in liver cell lines. RMI2 was overexpressed in hepatoma tissue and cell lines, and it promoted the migration and invasion of HCC cells. Moreover, RMI2 upregulated the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt3a/ß-catenin-related genes, but silencing RMI2 had the opposite effects. Notably, the expression of RMI2 was positively correlated with the clinical data of HCC patients who had significantly shorter overall survival (OS) and disease-free survival (DFS) (Both: P < 0.05). In addition, a total of 373 HCC patients' data from the Caner Genome Atlas project (TCGA) were used to validate our findings. CONCLUSIONS: Taking all these findings together, we determined that RMI2 was a new target gene of the Wnt/ß-catenin signaling pathway. We also found that RMI2 promotes EMT markers, HCC cell invasion, and metastasis, which indicated that RMI2 is a potential target for preventing or at least mitigating the progression of HCC.

[Anti-Restriction Activity of ArdB Protein against EcoAI Endonuclease].

ArdB proteins are known to inhibit the activity of the type I restriction-modification (RM-I) system, in particular EcoKI (IA family). The mechanism of ArdB's activity still remains unknown; the spectrum of targets inhibited has been poorly studied. In this work, it was shown that the presence of the ardB gene from the R64 plasmid could suppress the activity of EcoAI endonuclease (IB family) in Escherichia coli TG1 cells. Due to the absence of specificity of ArdB to a certain RM-I system (it inhibits both the IA- and IB-family), it can be assumed that the mechanism of the anti-restriction activity of this protein does not depend on the sequence DNA at the recognition site nor the structure of the restriction enzyme of the RM-I systems.

Accuracy of the risk of malignancy index-I in diagnosing ovarian malignancy in menopausal women.

Introduction: To detect the accuracy of the risk of malignancy index-I (RMI-I) in diagnosing ovarian malignancy in menopausal women. Material and methods: Eighty-two menopausal women with suspected ovarian masses (OMs) scheduled for surgery were included in this study. Blood samples were preoperatively collected from participants to measure the CA-125, followed by transvaginal sonography to evaluate the suspected OMs regarding the consistency, whether the OMs were unilateral or bilateral, unilocular or multilocular, and for extra-ovarian metastasis. The preoperative RMIs were compared to the postoperative histology of the excised OMs to detect the accuracy of RMI-I at a cut-off value of 200 in diagnosing ovarian malignancy. The receiver operating characteristic curve was also used to detect the cut-off value of RMI-I with the highest sensitivity and specificity in diagnosing ovarian malignancy in menopausal women. Results: The incidence of benign and malignant OMs in the studied menopausal women was 59.8% and 40.2%, respectively. The risk of malignancy index-I at a cut-off value 200 in this study had 75.8% sensitivity, 91.8% specificity, 86.2% positive predictive value (PPV), and 84.9% negative predictive value (NPV) in diagnosing ovarian malignancy in menopausal women. The receiver operating characteristic curve showed that the RMI-I at a cut-off value of > 241.5 had 96% sensitivity and 94.74% specificity in diagnosing ovarian malignancy in menopausal women (AUC 0.98, 95% CI: 0.92-0.99, p < 0.001). Conclusions: The risk of malignancy index I at a cut-off value of 200 had 75.8% sensitivity, 91.8% specificity, 86.2% PPV, and 84.9% NPV in diagnosing ovarian malignancy in menopausal women. The receiver operating characteristic curve showed that the RMI-I at a cut-off value > 241.5 had 96% sensitivity and 94.74% specificity in diagnosing ovarian malignancy in menopausal women.

Phenotypic spectrum of BLM- and RMI1-related Bloom syndrome.

Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS.

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

Blockchain Socket Factories with RMI-Enabled Framework for Fine-Grained Healthcare Applications.

The usage of digital and intelligent healthcare applications on mobile devices has grown progressively. These applications are generally distributed and access remote healthcare services on the user's applications from different hospital sources. These applications are designed based on client-server architecture and different paradigms such as socket, remote procedure call, and remote method invocation (RMI). However, these existing paradigms do not offer a security mechanism for healthcare applications in distributed mobile-fog-cloud networks. This paper devises a blockchain-socket-RMI-based framework for fine-grained healthcare applications in the mobile-fog-cloud network. This study introduces a new open healthcare framework for applied research purposes and has blockchain-socket-RMI abstraction level classes for healthcare applications. The goal is to meet the security and deadline requirements of fine-grained healthcare tasks and minimize execution and data validation costs during processing applications in the system. This study introduces a partial proof of validation (PPoV) scheme that converts the workload into the hash and validates it among mobile, fog, and cloud nodes during offloading, execution, and storing data in the secure form. Simulation discussions illustrate that the proposed blockchain-socket-RMI minimizes the processing and blockchain costs and meets the security and deadline requirements of fine-grained healthcare tasks of applications as compared to existing frameworks in work.

Potent Blockchain-Enabled Socket RPC Internet of Healthcare Things (IoHT) Framework for Medical Enterprises.

Present-day intelligent healthcare applications offer digital healthcare services to users in a distributed manner. The Internet of Healthcare Things (IoHT) is the mechanism of the Internet of Things (IoT) found in different healthcare applications, with devices that are attached to external fog cloud networks. Using different mobile applications connecting to cloud computing, the applications of the IoHT are remote healthcare monitoring systems, high blood pressure monitoring, online medical counseling, and others. These applications are designed based on a client-server architecture based on various standards such as the common object request broker (CORBA), a service-oriented architecture (SOA), remote method invocation (RMI), and others. However, these applications do not directly support the many healthcare nodes and blockchain technology in the current standard. Thus, this study devises a potent blockchain-enabled socket RPC IoHT framework for medical enterprises (e.g., healthcare applications). The goal is to minimize service costs, blockchain security costs, and data storage costs in distributed mobile cloud networks. Simulation results show that the proposed blockchain-enabled socket RPC minimized the service cost by 40%, the blockchain cost by 49%, and the storage cost by 23% for healthcare applications.

Molecular Biomarkers for the Early Detection of Ovarian Cancer.

Ovarian cancer is the deadliest gynecological cancer, leading to over 152,000 deaths each year. A late diagnosis is the primary factor causing a poor prognosis of ovarian cancer and often occurs due to a lack of specific symptoms and effective biomarkers for an early detection. Currently, cancer antigen 125 (CA125) is the most widely used biomarker for ovarian cancer detection, but this approach is limited by a low specificity. In recent years, multimarker panels have been developed by combining molecular biomarkers such as human epididymis secretory protein 4 (HE4), ultrasound results, or menopausal status to improve the diagnostic efficacy. The risk of ovarian malignancy algorithm (ROMA), the risk of malignancy index (RMI), and OVA1 assays have also been clinically used with improved sensitivity and specificity. Ongoing investigations into novel biomarkers such as autoantibodies, ctDNAs, miRNAs, and DNA methylation signatures continue to aim to provide earlier detection methods for ovarian cancer. This paper reviews recent advancements in molecular biomarkers for the early detection of ovarian cancer.

Morphological parameters of ovarian masses and accuracy of the risk of malignancy index in diagnosing ovarian malignancy.

Introduction: To detect the morphological parameters of ovarian masses and the accuracy of the risk of mali-gnancy index (RMI) in diagnosing ovarian malignancy. Material and methods: 264 women in 3 groups (reproductive, premenopausal, and postmenopausal) presented with ovarian masses and scheduled for surgery were included in this study. The participants' preoperative RMI was compared to the postoperative histology (gold standard) to detect the accuracy of RMI in diagnosing ovarian malignancy. Results: The incidence of malignant and benign ovarian tumours in the reproductive group was 9.1% and 90.9%, respectively, while it was 35.2% and 64.8%, respectively, in the premenopausal group, and 35.2%, and 64.8%, respectively, in the postmenopausal group. The incidence of malignant ovarian tumours was significantly higher in the premenopausal (35.2%) and postmenopausal (35.2%) groups compared to the reproductive group (9.1%), (p = 0.0008, and p = 0.0008, respectively).The receiver operating characteristic curve showed that RMI at cut-off value > 247.5 had 82.9% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 98.1% negative predictive value (NPV) in diagnosing ovarian malignancy in the 3 studied groups (AUC 0.955, p < 0.001). There was significant positive correlation between the participants' age, and RMI (p = 0.001), and between participants' cancer antigen-125 (CA-125) and RMI (p < 0.0001) in the ovarian malignancy group. Conclusions: The multimodal RMI is an effective tool for primary evaluation of suspected ovarian masses. Risk malignancy index at cut-off value > 247.5 had the best performance (82.9% sensitivity, 100% specificity, 100% PPV, and 98.1% NPV) in diagnosing ovarian malignancy in the 3 studied groups. There was significant positive correlation between participants' age, and RMI, and between participants' CA-125 and RMI, in the studied malignant ovarian tumours.

Scoring systems for the evaluation of adnexal masses nature: current knowledge and clinical applications.

Adnexal masses are a common finding in women, with 20% of them developing at least one pelvic mass during their lifetime. There are more than 30 different subtypes of adnexal tumours, with multiple different subcategories, and the correct characterisation of the pelvic masses is of paramount importance to guide the correct management. On that basis, different algorithms and scoring systems have been developed to guide the clinical assessment. The first scoring system implemented into the clinical practice was the Risk of Malignancy Index, which combines ultrasound evaluation, menopausal status, and serum CA-125 levels. Today, current guidelines regarding female patients with adnexal masses include the application of International Ovarian Tumours Analysis simple rules, logistic regression model 1 (LR1) and LR2, OVERA, cancer ovarii non-invasive assessment of treating strategy, and assessment of Different Neoplasias in the adnexa. In this scenario, the choice of the scoring system for the discrimination between benign and malignant ovarian tumours can be complex when approaching patients with adnexal masses. This review aims to summarise the available evidence regarding the different scoring systems to provide a complete overview of the topic.

Hepatocellular carcinoma in adult thalassemia patients: an expert opinion based on current evidence.

Beta-thalassemia represents a heterogeneous group of haemoglobin inherited disorders, among the most common genetic diseases in the world, frequent in the Mediterranean basin. As beta-thalassemia patients' survival has increased over time, previously unknown complications are observed with increasing frequency. Among them, an increased risk of hepatocellular carcinoma (HCC) has been registered. Our aim is to reduce inequalities in diagnosis and treatment and to offer patients univocal recommendations in any institution.The members of the panel - gastroenterologists, radiologists, surgeons and oncologists -were selected on the basis of their publication records and expertise. Thirteen clinical questions, derived from clinical needs, and an integration of all the committee members' suggestions, were formulated. Modified Delphi approach involving a detailed literature review and the collective judgement of experts, was applied to this work.Thirteen statements were derived from expert opinions' based on the current literature, on recently developed reviews and on technological advancements. Each statement is discussed in a short paragraph reporting the current key evidence. As this is an emerging issue, the number of papers on HCC in beta-thalassemia patients is limited and based on anecdotal cases rather than on randomized controlled studies. Therefore, the panel has discussed, step by step, the possible differences between beta-thalassemia and non beta-thalassemia patients. Despite the paucity of the literature, practical and concise statements were generated.This paper offers a practical guide organized by statements describing how to manage HCC in patients with beta-thalassemia.

miR-362 knock-down promotes proliferation and inhibits apoptosis in porcine immature Sertoli cells by targeting the RMI1 gene.

Immature Sertoli cell proliferation determines the total number of mature Sertoli cells and further regulates normal spermatogenesis. Accumulating evidence demonstrates that microRNAs (miRNAs) play regulatory roles in immature Sertoli cell proliferation, while the functions and mechanisms of the Sertoli cells of domestic animals are poorly understood. In the present study, we aimed to investigate the roles of miR-362 in cell proliferation and apoptosis of porcine immature Sertoli cells. The results showed that miR-362 inhibition promoted the entrance of cells into the S phase and increased the expressions of cell cycle-related genes c-MYC, CNNE1, CCND1 and CDK4. Knock-down of miR-362 also promoted cell proliferation and inhibited apoptosis, which was demonstrated by the results from cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and Annexin V-FITC/PI staining assays. The recQ-mediated genome instability protein 1 (RMI1) gene was identified as a potential target gene of miR-362 via luciferase reporter assay, and miR-362 repressed the protein expression of RMI1 in porcine immature Sertoli cells. siRNA-induced RMI1 knock-down further abolished the effects of miR-362 inhibition on porcine immature Sertoli cells. Collectively, we concluded that miR-362 knock-down promotes proliferation and inhibits apoptosis in porcine immature Sertoli cells by targeting the RMI1 gene, which indicates that miR-362 determines the fate of immature Sertoli cells.

RMI and ROMA are equally effective in discriminating between benign and malignant gynecological tumors: A prospective population-based study.

INTRODUCTION: Our primary objective was to test the hypothesis that human epididymal protein 4 (HE4) and risk of ovarian malignancy index outperform the CA 125 and risk of malignancy index tests in categorizing a pelvic mass into high or low risk of malignancy in a Swedish population. Furthermore, cut-off values needed to be defined for HE4 and ROMA in premenopausal and postmenopausal women prior to their introduction to clinical practice. A third objective was to investigate the correlation between HE4 levels in serum and urine. MATERIAL AND METHODS: Women with a pelvic mass scheduled for surgery were recruited from nine hospitals in south-east Sweden. Preoperative blood samples were taken for analyzing CA125 and HE4 as well as urine samples for analyzing HE4. RESULTS: We enrolled a total of 901 women, of whom 784 were evaluable. In the premenopausal and postmenopausal groups, no significant differences were found for sensitivity, positive and negative predictive value, either for RMI vs ROMA or for CA125 vs HE4 using a fixed specificity of 75%. Cut-off values indicating malignancy were established for HE4 and ROMA in premenopausal and postmenopausal women. We found no correlation between HE4 concentration in serum and urine. CONCLUSIONS: We could not confirm that ROMA had diagnostic superiority over RMI in categorizing women with a pelvic mass into low-risk or high-risk groups for malignancy in a Swedish population. We have defined cut-off values for HE4 and ROMA. The lack of correlation between serum and urine HE4 obviates the introduction of urine HE4 analysis in clinical diagnostics.

A multicenter clinical trial validating the performance of HE4, CA125, risk of ovarian malignancy algorithm and risk of malignancy index.

OBJECTIVE: To validate, in a multicenter clinical trial, the performance of biomarkers and algorithms for differential diagnosis in a population of women diagnosed with an unknown ovarian cyst or pelvic tumor. METHODS: Six hospitals in Western Sweden consecutively enrolled 638 women from September 2013 to February 2016. Serum, transvaginal ultrasound data, and basic patient characteristics were collected preoperatively. Biomarker levels, risk of malignancy algorithm (ROMA), and risk of malignancy index (RMI) were calculated and compared with the final pathology report. RESULTS: Our sample of 638 patients had 445 benign, 31 borderline, and 162 malignant tumors recorded, and the overall incidence of epithelial ovarian cancer was 21%. In postmenopausal women, RMI (>200), ROMA (≥29.9), CA125 (>35 U/mL), and HE4 (>140 pmol/L) showed sensitivity at 89%, 91%, 92%, and 72%, respectively, and specificity at 80%, 77%, 80%, and 92%. In premenopausal women, sensitivity of RMI, ROMA (≥11.6), CA125, and HE4 (>70 pmol/L) was 87%, 87%, 96%, and 83%, respectively, and specificity was 90%, 81%, 60%, 91%. Diagnostic accuracy (ROC AUC) of RMI and ROMA in postmenopausal women was 0.85 and 0.84, and in premenopausal women, 0.90 and 0.81. CONCLUSION: Our results suggest that CA125 is superior to HE4 as a biomarker to identify women with ovarian cancer. HE4 more correctly identifies benign lesions, which may help in differential diagnoses to guide the level of care and decrease overtreatment. This study confirms prior results from single-center studies and suggests the implementation of HE4 measurement in daily practice.

Discriminative value of CA-125, HE4, Risk of Malignancy Index II (RMI-II) and Risk of Malignancy Algorithm (ROMA) in the differential diagnosis of pelvic masses: conclusions from a referral Centre in Portugal.

The major purpose of this article was to compare the discriminative value of different algorithms and serum biomarkers in the differential diagnosis of adnexal masses. We performed a retrospective study with 247 women with adnexal neoplasia, submitted to surgical treatment and with a histological diagnosis. The evaluation of the area under the curve (AUC) for isolated CA-125 and HE4, and for ROMA and RMI-II, showed a better specificity of HE4 and RMI-II in premenopausal women. In the postmenopausal group, ROMA and RMI-II were the algorithms with a better performance. Impact Statement What is already known on this subject? CA-125 remains the most commonly used biomarker used to predict the behaviour of an adnexal mass, but it has a low sensitivity for stage I tumours. Other isolated serum markers have emerged more recently, such as HE4, as well as more complex algorithms, such as RMI or ROMA. It remains unclear which is the best marker/algorithm to predict the behaviour of an adnexal mass. What do the results of this study add? Our findings showed that ROMA is a suitable marker for postmenopausal women, with no advantage found in the premenopausal women when compared with an isolated HE4. What are the implications of these findings for clinical practice and/or further research? The different algorithms of the preoperative discrimination of ovarian neoplasia appear to have different AUC, SN and SP in the pre- or the postmenopausal patients. For the premenopausal women, the use of ROMA does not seem to have any advantage over the isolated use of HE4, which does not lose specificity even when the borderline tumours are considered for discrimination. In the postmenopausal women, ROMA is a valid algorithm with a good sensitivity. The RMI-II showed a good performance in both groups, although it depends on the ultrasound findings and has an important interobserver variability. This information allows a more targeted selection of markers and algorithms to be requested prior to surgery of ovarian neoplasms regarding the menopausal status of each patient.

Knockdown of RMI1 impairs DNA repair under DNA replication stress.

RMI1 (RecQ-mediated genome instability protein 1) forms a conserved BTR complex with BLM, Topo IIIα, and RMI2, and its absence causes genome instability. It has been revealed that RMI1 localizes to nuclear foci with BLM and Topo IIIα in response to replication stress, and that RMI1 functions downstream of BLM in promoting replication elongation. However, the precise functions of RMI1 during replication stress are not completely understood. Here we report that RMI1 knockdown cells are hypersensitive to hydroxyurea (HU). Using comet assay, we show that RMI1 knockdown cells exhibit accumulation of broken DNAs after being released from HU treatment. Moreover, we demonstrate that RMI1 facilitates the recovery from activated checkpoint and resuming the cell cycle after replicative stress. Surprisingly, loss of RMI1 results in a failure of RAD51 loading onto DNA damage sites. These findings reveal the importance of RMI1 in response to replication stress, which could explain the molecular basis for its function in maintaining genome integrity.

Estimating risk of malignancy in adnexal masses: external validation of the ADNEX model and comparison with other frequently used ultrasound methods.

OBJECTIVES: To validate externally the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model and compare this model with other frequently used models in the differentiation between benign and malignant adnexal masses. METHODS: In this retrospective diagnostic accuracy study, we assessed data collected prospectively from patients with adnexal pathology who underwent real-time transvaginal or transrectal ultrasound by a single expert ultrasonographer in a tertiary care hospital between July 2011 and July 2015. The presence of a malignancy was determined by subjective assessment and use of four prediction models: the ADNEX model, simple ultrasound-based rules (simple rules), Logistic Regression model 2 (LR2) and the Risk of Malignancy Index (RMI), of which three different variants were assessed. Pathology was the clinical reference standard. RESULTS: In total, 851 consecutive patients underwent ultrasound examination for an adnexal mass. For 326 patients (128 premenopausal and 198 postmenopausal), pathology results were available (211 (64.7%) benign; 115 (35.3%) malignant) and these were included in the analysis. The area under the receiver-operating characteristics curve (AUC) of the ADNEX model for the discrimination between benign and malignant tumors was 0.93 (95% CI, 0.89-0.95). AUCs for the subtypes of malignancy (i.e. borderline, Stage I-IV and metastatic adnexal tumors) ranged between 0.60 and 0.90. Only subjective assessment (AUC, 0.96 (95% CI, 0.93-0.98)) was superior to the ADNEX model (P = 0.01) in differentiating malignant from benign tumors. AUCs for the other models were 0.92 (95% CI, 0.89-0.95) for LR2, 0.85 (95% CI, 0.81-0.89) for RMI-I, 0.82 (95% CI, 0.77-0.86) for RMI-II and 0.84 (95% CI, 0.80-0.88) for RMI-III. At the proposed cut-off of ≥ 10%, the ADNEX model had the highest sensitivity (0.98 (95% CI, 0.93-1.00)) but the lowest specificity (0.62 (95% CI, 0.55-0.68)) compared with the other models. Both subjective assessment (sensitivity, 0.90 (95% CI, 0.83-0.95); specificity 0.91 (95% CI, 0.86-0.94)) and the simple rules model with inconclusive cases classified by subjective assessment (sensitivity, 0.89 (95% CI, 0.81-0.94); specificity, 0.90 (95% CI, 0.85-0.94)) had lower sensitivity, but their sensitivity and specificity were better balanced. CONCLUSIONS: Although the test performance of subjective assessment by an expert remains superior, the ADNEX model can help in the differentiation between benign and malignant ovarian tumors. The advantage of the ADNEX model as a polytomous model remains to be shown. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.