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AbstractBackground and AimsInflammatory bowel diseases are linked to an increased risk of developing colorectal cancer [CRC]. Previous studies suggested that the H2B ubiquitin ligase RING finger protein-20 [RNF20] inhibited inflammatory signaling mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB]. However, the role of RNF40, the obligate heterodimeric partner of RNF20, in the context of inflammation and CRC has not been addressed. Here, we examined the effect of RNF40 loss on CRC cells in vitro and on inflammation and inflammatory signaling in vitro and in vivo.MethodsWe evaluated H2Bub1 levels in human and murine colorectal tumors by immunohistochemistry. Moreover, we correlated H2Bub1 and RNF40 levels in vivo and assessed the consequences of RNF40 depletion on cellular phenotype and gene expression in CRC cells in vitro. Finally, we examined the effect of a colon-specific loss of Rnf40 in a murine model of colitis, and assessed both local and systemic inflammation-associated consequences.ResultsIn vitro studies revealed that the tumorigenic phenotype of CRC cells decreased after RNF40 depletion and displayed gene expression changes related to chromosome segregation and DNA replication, as well as decreased induction of several NF-κB-associated cytokines. This effect was associated with decreased nuclear localization of NF-κB following tumor necrosis factor alpha treatment. Consistently, the colon-specific loss of Rnf40 exerted a protective local, as well as systemic, effect following acute colitis.ConclusionsOur findings suggest that RNF40 plays a central role in the maintenance of tumorigenic features and inflammatory signaling by promoting nuclear NF-κB activity.

Background The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. Methods We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. Results At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. Conclusions AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive sequelae, and has not been investigated for its immunostimulatory effects. Furthermore, WBRT exposes the entire intracranial tumor immune microenvironment to radiation. SRS delivers a high dose of conformal radiation with image guidance to minimize dose to surrounding normal brain tissue, and appears to promote anti-tumor immunity. In parallel with many of these discoveries, immune checkpoint inhibitors (ICIs) have demonstrated a survival advantage in multiple malignancies commonly associated with brain metastases (e.g., melanoma). Combination SRS and ICI are theorized to be synergistic in anti-tumor immunity directed to brain metastases. The purpose of this review is to explore the synergy of SRS and ICIs, including pre-clinical data, existing clinical data, and ongoing prospective trials.

ObjectivesThe aim of this study was to investigate the reproducibility of a standardized method to assess the ultrasound liver‐to‐thoracic area ratio in fetuses with congenital diaphragmatic hernia.MethodsWe selected 24 images of 9 fetuses diagnosed with left‐sided at our institution between January 2010 and December 2017. Eight operators (1 maternal‐fetal medicine specialist and 7 sonographers) reviewed the selected images and assessed the ultrasound liver‐to‐thoracic area ratio according to a standardized protocol. We evaluated the correlation between operators using the intraclass correlation coefficient and compared agreement between the sonographers and a physician with experience in measuring the ultrasound liver‐to‐thoracic area ratio using a Bland‐Altman analysis.ResultsGood intraoperator reproducibility was observed for the standardized ultrasound liver‐to‐thoracic area ratio (intraclass correlation coefficient, 0.78). Good agreement among sonographers and the physician was also observed for the standardized measurements (bias, 0.01; precision, 0.03; limits of agreement, –0.05 to + 0.07).ConclusionsWe demonstrated that good intraoperator and interoperator reproducibility of ultrasound liver‐to‐thoracic area ratio assessment is feasible after standardizing the method in our center.

The optimal antithrombotic treatment regimen for patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation represents a challenge in clinical practice. In 2016, an updated opinion of selected experts from the United States and Canada on the treatment of patients with atrial fibrillation undergoing percutaneous coronary intervention was reported. After the 2016 North American consensus statement on the management of antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention, results of pivotal clinical trials assessing the type of oral anticoagulant agent and the duration of antiplatelet treatment have been published. On the basis of these results, this focused update on the antithrombotic management of patients with atrial fibrillation undergoing percutaneous coronary intervention recommends that a non–vitamin K antagonist oral anticoagulant be preferred over a vitamin K antagonist as the oral anticoagulant of choice. Moreover, a double-therapy regimen (oral anticoagulant plus single antiplatelet therapy with a P2Y 12 inhibitor) by the time of hospital discharge should be considered for most patients, whereas extending the use of aspirin beyond hospital discharge (ie, triple therapy) should be considered only for selected patients at high ischemic/thrombotic and low bleeding risks and for a limited period of time. The present document provides a focused updated on the rationale for the new expert consensus–derived recommendations on the antithrombotic management of patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention.