Understanding YTHDF2-mediated mRNA degradation by m6A-BERT-Deg.

N6-methyladenosine (m6A) is the most abundant mRNA modification within mammalian cells, holding pivotal significance in the regulation of mRNA stability, translation and splicing. Furthermore, it plays a critical role in the regulation of RNA degradation by primarily recruiting the YTHDF2 reader protein. However, the selective regulation of mRNA decay of the m6A-methylated mRNA through YTHDF2 binding is poorly understood. To improve our understanding, we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated degradation of m6A-methylated mRNAs. We meticulously assembled a high-quality training dataset by integrating multiple data sources for the HeLa cell line. To overcome the limitation of small training samples, we employed a pre-training-fine-tuning strategy by first performing a self-supervised pre-training of the model on 427 760 unlabeled m6A site sequences. The test results demonstrated the importance of this pre-training strategy in enabling m6A-BERT-Deg to outperform other benchmark models. We further conducted a comprehensive model interpretation and revealed a surprising finding that the presence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediated mRNA degradation, subsequently enhancing mRNA stability. We also extended our analyses to the HEK293 cell line, shedding light on the context-dependent YTHDF2-mediated mRNA degradation.

Combined hepatic resection and ablation for high burden of colorectal liver metastases demonstrates safety and durable survival.

BACKGROUND: Hepatic resection (HR) and thermal ablation of Colorectal Liver Metastases (CRLM) have each individually demonstrated safety and survival benefit. We sought to provide our experience with the combination of HR + ablation within one operation for patients with multiple CRLM. METHODS: Review of a single institution database of patients who underwent HR + ablation between 2010 and 2019. RESULTS: 161 patients were identified who underwent HR + ablation for isolated CRLM (mean age: 59, male 63.4%). 125 (77.6%) patients had bilobar disease and 92 (57.1%) patients had ≥5 tumors. 28 (17.4%) patients experienced minor (grade 1 or 2) complications while 20 (12.4%) had grade 3-5 complications. Patients who underwent simultaneous colon resection with HR + ablation had a higher complication rate (22 of 47, 46.8%) than those undergoing HR + ablation only (26 of 114, 22.8%, p = 0.002). Median and 5-year OS for all patients undergoing HR + ablation was 38.2 months and 33.2%, respectively. 5-year hepatic recurrence free survival was 23.5%. Patients with 5 or more tumors demonstrated no difference in median survival compared to those with fewer than 5 tumors (37.0 months vs 38.4 months, p = 0.326). CONCLUSIONS: In this population of CRLM patients with a relatively high burden of disease, HR + ablation demonstrated an acceptable safety profile as well as durable long-term survival.

Tumor microenvironment in a minipig model of spinal cord glioma.

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1ß, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.

CT-based Bosniak classification of cystic renal lesions: is version 2019 an improvement on version 2005?

OBJECTIVE: To compare the diagnostic performance and inter-reader agreement of the CT-based v2019 versus v2005 Bosniak classification systems for risk stratification of cystic renal lesions (CRL). METHODS: This retrospective study included adult patients with CRL identified on CT scan between 2005 and 2018. The reference standard was histopathology or a minimum 4-year imaging follow-up. The studies were reviewed independently by five readers (three senior, two junior), blinded to pathology results and imaging follow-up, who assigned Bosniak categories based on the 2005 and 2019 versions. Diagnostic performance of v2005 and v2019 Bosniak classifications for distinguishing benign from malignant lesions was calculated by dichotomizing CRL into the potential for ablative therapy (III-IV) or conservative management (I-IIF). Inter-reader agreement was calculated using Light's Kappa. RESULTS: One hundred thirty-nine patients with 149 CRL (33 malignant) were included. v2005 and v2019 Bosniak classifications achieved similar diagnostic performance with a sensitivity of 91% vs 91% and a specificity of 89% vs 88%, respectively. Inter-reader agreement for overall Bosniak category assignment was substantial for v2005 (κ = 0.78) and v2019 (κ = 0.75) between senior readers but decreased for v2019 when the Bosniak classification was dichotomized to conservative management (I-IIF) or ablative therapy (III-IV) (0.80 vs 0.71, respectively). For v2019, wall thickness was the morphological feature with the poorest inter-reader agreement (κ = 0.43 and 0.18 for senior and junior readers, respectively). CONCLUSION: No significant improvement in diagnostic performance and inter-reader agreement was shown between v2005 and v2019. The observed decrease in inter-reader agreement in v2019 when dichotomized according to management strategy may reflect the more stringent morphological criteria. KEY POINTS: • Versions 2005 and 2019 Bosniak classifications achieved similar diagnostic performance, but the specificity of higher risk categories (III and IV) was not increased while one malignant lesion was downgraded to v2019 Bosniak category II (i.e., not subjected to further follow-up). • Inter-reader agreement was similar between v2005 and v2019 but moderately decreased for v2019 when the Bosniak classification was dichotomized according to the potential need for ablative therapies (I-II-IIF vs III-IV).

Practical Tips for Reporting Adnexal Lesions Using O-RADS MRI.

The Ovarian-Adnexal Reporting and Data System (O-RADS) MRI risk stratification system provides a standardized lexicon and evidence-based risk score for evaluation of adnexal lesions. The goals of the lexicon and risk score are to improve report quality and communication between radiologists and clinicians, reduce variability in the reporting language, and optimize management of adnexal lesions. The O-RADS MRI risk score is based on the presence or absence of specific imaging features, including the lipid content, enhancing solid tissue, number of loculi, and fluid type. The probability of malignancy ranges from less than 0.5% when there are benign features to approximately 90% when there is solid tissue with a high-risk time-intensity curve. This information can aid in optimizing management of patients with adnexal lesions. The authors present an algorithmic approach to the O-RADS MRI risk stratification system and highlight key teaching points and common pitfalls. © RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Association between history of childbirth and chronic, functionally significant back pain in later life.

BACKGROUND: Back pain is more prevalent among women than men. The association with sex could be related to pregnancy and childbirth, unique female conditions. This association has not been thoroughly evaluated. METHODS: Using a retrospective cohort design, we evaluated the relationship between history of childbirth on the prevalence and severity of functionally consequential back pain in 1069 women from a tertiary care pain management clinic. Interactions among preexisting, acute peripartum, and subsequent back pain were evaluated as secondary outcomes among the parous women using logistic and linear regression as appropriate. RESULTS: The women who had given birth had a higher risk for functionally significant back pain compared to women who had not given birth (85% vs 77%, p < 0.001, Risk Ratio 1.11 [1.04-1.17]). The association was preserved after correction for age, weight, and race. Back pain was also more slightly severe (Numerical Rating Score for Pain 7[5-8] vs 6[5-7] out of 10, p = 0.002). Women who recalled severe, acute postpartum back pain had a higher prevalence of current debilitating back pain (89% vs 75%, Risk Ratio 1.19 (1.08-1.31), p = 0.001). Twenty-eight percent of acute postpartum back pain never resolved and 40% reported incomplete resolution. CONCLUSIONS: A history of pregnancy and childbirth is a risk factor for chronic functionally significant back pain in women. Severe acute postpartum back pain is a risk factor for future disability suggesting that the peripartum period may provide an important opportunity for intervention. Early recognition and management may mitigate future disability. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov as "Association Between Chronic Headache and Back Pain with Childbirth" (NCT04091321) on 16/09/2019 before it was initiated.

AI-Based Automated Lipomatous Tumor Segmentation in MR Images: Ensemble Solution to Heterogeneous Data.

Deep learning (DL) has been proposed to automate image segmentation and provide accuracy, consistency, and efficiency. Accurate segmentation of lipomatous tumors (LTs) is critical for correct tumor radiomics analysis and localization. The major challenge of this task is data heterogeneity, including tumor morphological characteristics and multicenter scanning protocols. To mitigate the issue, we aimed to develop a DL-based Super Learner (SL) ensemble framework with different data correction and normalization methods. Pathologically proven LTs on pre-operative T1-weighted/proton-density MR images of 185 patients were manually segmented. The LTs were categorized by tumor locations as distal upper limb (DUL), distal lower limb (DLL), proximal upper limb (PUL), proximal lower limb (PLL), or Trunk (T) and grouped by 80%/9%/11% for training, validation and testing. Six configurations of correction/normalization were applied to data for fivefold-cross-validation trainings, resulting in 30 base learners (BLs). A SL was obtained from the BLs by optimizing SL weights. The performance was evaluated by dice-similarity-coefficient (DSC), sensitivity, specificity, and Hausdorff distance (HD95). For predictions of the BLs, the average DSC, sensitivity, and specificity from the testing data were 0.72 [Formula: see text] 0.16, 0.73 [Formula: see text] 0.168, and 0.99 [Formula: see text] 0.012, respectively, while for SL predictions were 0.80 [Formula: see text] 0.184, 0.78 [Formula: see text] 0.193, and 1.00 [Formula: see text] 0.010. The average HD95 of the BLs were 11.5 (DUL), 23.2 (DLL), 25.9 (PUL), 32.1 (PLL), and 47.9 (T) mm, whereas of SL were 1.7, 8.4, 15.9, 2.2, and 36.6 mm, respectively. The proposed method could improve the segmentation accuracy and mitigate the performance instability and data heterogeneity aiding the differential diagnosis of LTs in real clinical situations.

MRI of Adenomyosis: Where Are We Today?

Purpose of Review: The purpose of this review is to (i) summarize the current literature regarding the role of magnetic resonance imaging (MRI) in diagnosing adenomyosis, (ii) examine how to integrate MRI phenotypes with clinical symptomatology and histological findings, (iii) review recent advances including proposed MRI classifications, (iv) discuss challenges and pitfalls of diagnosing adenomyosis, and (v) outline the future role of MRI in promoting a better understanding of the pathogenesis, diagnosis, and treatment options for patients with uterine adenomyosis. Recent Findings: Recent advances and the widespread use of MRI have provided new insights into adenomyosis and the range of imaging phenotypes encountered in this disorder. Summary: Direct and indirect MRI features allow for accurate non-invasive diagnosis of adenomyosis. Adenomyosis is a complex and poorly understood disorder with variable MRI phenotypes that may be correlated with different pathogeneses, clinical presentations, and patient outcomes. MRI is useful for the assessment of the extent of findings, to evaluate for concomitant gynecological conditions, and potentially can help with the selection and implementation of therapeutic options. Nevertheless, important gaps in knowledge remain. This is in part due to the lack of standardized criteria for reporting resulting in heterogeneous and conflicting data in the literature. Thus, there is an urgent need for a unified MRI reporting system incorporating standardized terminology for diagnosing adenomyosis and defining the various phenotypes.

Osteolytic sarcoidosis of the orbit without pulmonary involvement.

A 69-year-old woman with a history of a left orbital mass presented to the emergency room with progressive breakthrough pain in her left orbit despite medical therapy. On examination, there was extraocular motility restriction with diplopia upon left supraduction. Computed tomography (CT) scan of the orbits revealed soft tissue thickening of the left medial and superior periorbita and left lacrimal fossa; bony erosion of the left frontal bone, left orbital roof, and left lamina papyracea; and bilateral mass-like enlargement of the extraocular muscles. An orbitotomy with incisional biopsy was performed, and histopathological examination revealed non-caseating granulomatous inflammation consistent with sarcoidosis. Chest imaging demonstrated no sequela of pulmonary sarcoidosis, and her serum angiotensin converting enzyme (ACE) level was within normal range. She was treated with high-dose oral steroids with resolution of her symptoms. Her pain returned at the conclusion of the steroid taper, and it was controlled with chronic subcutaneous methotrexate and adalimumab injections.

Association of intraoperative dexmedetomidine use with postoperative hypotension in unilateral hip and knee arthroplasties: a historical cohort study.

PURPOSE: Dexmedetomidine is frequently used as a sedative agent for orthopedic surgery patients undergoing total hip or knee arthroplasty. Although the benefits of dexmedetomidine are well described in the literature, there is also potential for harm, especially regarding the hemodynamic effects of dexmedetomidine in the postoperative setting. METHODS: This historical cohort study included all primary unilateral total hip or knee arthroplasties conducted from April 2017 to February 2020 in a single, university-affiliated, tertiary care centre (Jewish General Hospital, Montreal, QC, Canada). We used multivariable logistic regression to analyze the predictors for postoperative hypotension, defined as a systolic blood pressure < 90 mm Hg or any systolic blood pressure while on a vasopressor infusion in the postanesthesia care unit. Models were validated using calibration and discrimination with bootstrapping technique. RESULTS: One thousand five hundred and eighty-eight patients were included in this study. Postoperative hypotension occurred in 413 (26%) patients. Statistically significant predictors for postoperative hypotension included female sex (adjusted odds ratio [aOR], 3.24; 95% confidence interval [CI], 2.29 to 4.58), a history of transient ischemic attack or cerebrovascular accident (aOR, 1.97; 95% CI, 1.04 to 3.72), and intraoperative dexmedetomidine use (aOR, 2.61; 95% CI, 1.99 to 3.42). Moreover, the risk of postoperative hypotension was approximately two times higher than baseline, with a total intraoperative dexmedetomidine dose above 50 µg (relative risk, 1.99; 95% CI, 1.63 to 2.44; P < 0.001). A higher preoperative systolic blood pressure (aOR, 0.98; 95% CI, 0.97 to 0.99) was a protective factor for postoperative hypotension. CONCLUSION: In this historical cohort study, dexmedetomidine was a strong risk factor for postoperative hypotension in total hip or knee arthroplasty patients. Dexmedetomidine, and particularly at high cumulative doses above 50 µg, should be administered judiciously in high-risk surgical patients to minimize the risk of postoperative hypotension.

RéSUMé: OBJECTIF: La dexmédétomidine est fréquemment utilisée comme agent sédatif pour les patients en chirurgie orthopédique bénéficiant d'une arthroplastie totale de la hanche ou du genou. Bien que les avantages de la dexmédétomidine soient bien décrits dans la littérature, il existe également un potentiel de préjudice, en particulier en ce qui touche aux effets hémodynamiques de la dexmédétomidine dans un contexte postopératoire. MéTHODE: Cette étude de cohorte historique comprenait toutes les arthroplasties totales unilatérales primaires de la hanche ou du genou réalisées entre avril 2017 et février 2020 dans un seul centre de soins tertiaires universitaire (Hôpital général juif, Montréal, QC, Canada). Nous avons utilisé la régression logistique multivariable pour analyser les prédicteurs d'hypotension postopératoire, définie comme une tension artérielle systolique < 90 mmHg ou toute tension artérielle systolique pendant une perfusion de vasopresseurs en salle de réveil. Les modèles ont été validés à l'aide de l'étalonnage et de la discrimination avec une technique d'auto-amorçage. RéSULTATS: Mille cinq cent quatre-vingt-huit patients ont été inclus dans cette étude. Une hypotension postopératoire est survenue chez 413 (26 %) patients. Les prédicteurs statistiquement significatifs d'une hypotension postopératoire comprenaient le sexe féminin (rapport de cotes ajusté [RCA], 3,24; intervalle de confiance [IC] à 95 %, 2,29 à 4,58), des antécédents d'accident ischémique transitoire ou d'accident vasculaire cérébral (RCA, 1,97; IC 95 %, 1,04 à 3,72) et l'utilisation peropératoire de dexmédétomidine (RCA, 2,61; IC 95 %, 1,99 à 3,42). De plus, le risque d'hypotension postopératoire était environ deux fois plus élevé que la valeur initiale, avec une dose peropératoire totale de dexmédétomidine supérieure à 50 µg (risque relatif, 1,99; IC 95 %, 1,63 à 2,44; P < 0,001). Une tension artérielle systolique préopératoire plus élevée (RCA, 0,98; IC 95 %, 0,97 à 0,99) était un facteur protecteur contre l'hypotension postopératoire. CONCLUSION: Dans cette étude de cohorte historique, la dexmédétomidine était un facteur de risque important d'hypotension postopératoire chez les patients bénéficiant d'une arthroplastie totale de la hanche ou du genou. La dexmédétomidine, et en particulier à des doses cumulatives élevées supérieures à 50 µg, devrait être administrée judicieusement chez les patients chirurgicaux à haut risque afin de minimiser le risque d'hypotension postopératoire.

Online measures of looking and learning in infancy.

Infants in laboratory settings look longer at events that violate their expectations, learn better about objects that behave unexpectedly, and match utterances to the objects that likely elicited them. The paradigms revealing these behaviors have become cornerstones of research on preverbal cognition. However, little is known about whether these canonical behaviors are observed outside laboratory settings. Here, we describe a series of online protocols that replicate classic laboratory findings, detailing our methods throughout. In Experiment 1a, 15-month-old infants (N = 24) looked longer at an online support event culminating in an Unexpected outcome (i.e., appearing to defy gravity) than an Expected outcome. Infants did not, however, show the same success with an online solidity event. In Experiment 1b, 15-month-old infants (N = 24) showed surprise-induced learning following online events-they were better able to learn a novel object's label when the object had behaved unexpectedly compared to when it behaved expectedly. Finally, in Experiment 2, 16-month-old infants (N = 20) who heard a valenced utterance ("Yum!") showed preferential looking to the object most likely to have generated that utterance. Together, these results suggest that, with some adjustments, online testing is a feasible and promising approach for infant cognition research.

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

BACKGROUND: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. METHODS: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. RESULTS: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. CONCLUSIONS: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.

The Effect of Steroids in Patients Undergoing Cardiopulmonary Bypass: An Individual Patient Meta-Analysis of Two Randomized Trials.

OBJECTIVE: Steroids suppress the inflammatory response to cardiopulmonary bypass, but the impact on death at 30 days, myocardial infarction or injury, stroke, renal failure, respiratory failure, new atrial fibrillation, transfusion requirement, infection, and length of intensive care unit (ICU) and hospital stays are uncertain. DESIGN: Patient-level data meta-analysis of 2 randomized trials. SETTING: Eighty-eight cardiac surgical centers in 19 countries. PARTICIPANTS: A total of 11,989 participants, from the Steroids in Cardiac Surgery trial and the Dexamethasone in Cardiac Surgery study, undergoing cardiac surgery with the use of cardiopulmonary bypass. INTERVENTIONS: Participants were randomly assigned to steroid or placebo. MEASURES AND MAIN RESULTS: Outcomes assessed were mortality at 30 days, myocardial infarction or injury, stroke, renal failure, respiratory failure, new atrial fibrillation, transfusion requirement, infection, and length of ICU and hospital stays. There was no significant difference in death at 30 days between the steroid and placebo groups (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.72-1.07). Myocardial infarction did not differ significantly (OR, 1.17; 95% CI, 0.93-1.47); however, myocardial injury was higher in the steroid group (OR, 1.25; 95% CI, 1.12-1.40). There were no significant differences for the outcomes of stroke, renal failure, new atrial fibrillation, or transfusion. Steroids significantly reduced respiratory failure (OR, 0.83; 95% CI, 0.75-0.99), infection (OR, 0.80; 95% CI, 0.72-0.89), and length of ICU (p < 0.001) and hospital stays (p = 0.006). CONCLUSIONS: This patient-level meta-analysis does not support the routine use of steroids in cardiac surgery. Steroid administration did not decrease the risk of death, myocardial infarction, stroke, renal failure, new atrial fibrillation, or transfusion. Steroids increased the risk of myocardial injury in both the Steroids in Cardiac Surgery and Dexamethasone in Cardiac Surgery trials. Finally, steroids lowered the risk of respiratory failure and infection, and reduced length of ICU and hospital stay.

Qualitative evaluation of MRI features of lipoma and atypical lipomatous tumor: results from a multicenter study.

OBJECTIVES: The objectives of the study are (1) to distinguish lipoma (L) from atypical lipomatous tumor (ALT) using MRI qualitative features, (2) to assess the value of contrast enhancement, and (3) to evaluate the reproducibility and confidence level of radiological readings. MATERIALS AND METHODS: Patients with pathologically proven L or ALT, who underwent MRI within 3 months from surgical excision were included in this retrospective multicenter international study. Two radiologists independently reviewed MRI centrally. Impressions were recorded as L or ALT. A third radiologist was consulted for discordant readings. The two radiologists re-read all non-contrast sequences; impression was recorded; then post-contrast images were reviewed and any changes were recorded. RESULTS: A total of 246 patients (135 females; median age, 59 years) were included. ALT was histopathologically confirmed in 70/246 patients. In multivariable analysis, in addition to the lesion size, deep location, proximal lower limb lesions, demonstrating incomplete fat suppression, or increased architectural complexity were the independent predictive features of ALT; but not the contrast enhancement. Post-contrast MRI changed the impression in a total of 5 studies (3 for R1 and 4 for R2; 2 studies are common); all of them were incorrectly changed from Ls to ALTs. Overall, inter-reader kappa agreement was 0.42 (95% CI 0.39-0.56). Discordance between the two readers was statistically significant for both pathologically proven L (p < 0.001) and ALT (p = 0.003). CONCLUSION: Most qualitative MR imaging features can help distinguish ALTs from BLs. However, contrast enhancement may be limited and occasionally misleading. Substantial discordance on MRI readings exists between radiologists with a relatively high false positive and negative rates.

Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking.

Relapse to non-medical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction-induced abstinence. We also determined the role of mu, delta and kappa opioid receptors (MOR, DOR, KOR) in this reinstatement. We trained rats to self-administer oxycodone for 6 h/day in context A; lever pressing was paired with a discrete cue. Next, we extinguished the lever pressing in the presence of the discrete cue in context B and then tested the rats for reinstatement of oxycodone seeking in both contexts. We retrained rats to self-administer oxycodone in context A, re-extinguished their lever pressing in context B and retested them for reinstatement in both contexts. Prior to testing, we injected the rats with vehicle or antagonists of MOR (naltrexone; 0.5 or 1.0 mg/kg), DOR (naltrindole; 7.5 or 15 mg/kg) or KOR (LY2456302; 5 or 10 mg/kg). We also tested the effect of naltrexone, naltrindole and LY2456302 on oxycodone self-administration under fixed-ratio-1 (FR1) and progressive ratio (PR) reinforcement schedules. We observed context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction. Naltrexone, but not naltrindole or LY2456302, injections decreased this reinstatement. Additionally, naltrexone increased oxycodone self-administration under the FR1 schedule and decreased oxycodone self-administration under the PR schedule; naltrindole and LY2456302 were ineffective. Results demonstrate a critical role of MOR, but not DOR or KOR, in context-induced reinstatement of oxycodone seeking and oxycodone self-administration.

Value of Increasing Biopsy Cores per Target with Cognitive MRI-targeted Transrectal US Prostate Biopsy.

Purpose To determine the increase in clinically significant cancer detection in the prostate with increasing number of core samples obtained by using cognitive MRI-targeted transrectal US biopsy. Materials and Methods This retrospective cross-sectional study included 330 consecutive patients (mean age, 64.3 years; range, 42-84 years) who underwent multiparametric prostate MRI from March 2012 to July 2017 and had an index lesion that subsequently underwent cognitive MRI-targeted biopsy using transrectal US with at least five core samples (which were sequentially labeled) per lesion. The detection rate of clinically significant cancer was calculated on sequential biopsy cores, comparing the first core alone versus three cores versus five cores per target. Clinically significant cancer was defined as International Society of Urological Pathology Grade Group 2 or higher. Results Increasing the number of biopsy core samples from one to three per target and from three to five per target increased the detection rate of clinically significant cancer by 6.4% (21 of 330) and 2.4% (eight of 330), respectively. The target yield for clinically significant cancer was 26% (87 of 330), 33% (108 of 330), and 35% (116 of 330) for one, three, and five cores, respectively. Subgroup analysis showed no significant difference in upgrade rates as a function of multiparametric MRI lesion size (P = .53-.59) or location (P = .28-.89). Conclusion More clinically significant prostate cancers are detected when increasing the number of core biopsy samples per index lesion from one to three and from three to five (6.4% and 2.4%, respectively) when performing cognitive MRI-targeted transrectal US biopsy. © RSNA, 2019 See also the editorial by Oto in this issue.

A multiparametric [18F]FDG PET/MRI diagnostic model including imaging biomarkers of the tumor and contralateral healthy breast tissue aids breast cancer diagnosis.

PURPOSE: To develop a multiparametric [18F]FDG positron emission tomography/magnetic resonance imaging (PET/MRI) model for breast cancer diagnosis incorporating imaging biomarkers of breast tumors and contralateral healthy breast tissue. METHODS: In this prospective study and retrospective data analysis, 141 patients (mean 57 years) with an imaging abnormality detected on mammography and/or ultrasound (BI-RADS 4/5) underwent combined multiparametric [18F]FDG PET/MRI with PET/computed tomography and multiparametric MRI of the breast at 3 T. Images were evaluated and the following were recorded: for the tumor, BI-RADS descriptors on dynamic contrast-enhanced (DCE)-MRI, mean apparent diffusion co-efficient (ADCmean) on diffusion-weighted imaging (DWI), and maximum standard uptake value (SUVmax) on [18F]FDG-PET; and for the contralateral healthy breast, background parenchymal enhancement (BPE) and amount of fibroglandular tissue (FGT) on DCE-MRI, ADCmean on DWI, and SUVmax. Histopathology served as standard of reference. Uni-, bi-, and multivariate logistic regression analyses were performed to assess the relationships between malignancy and imaging features. Predictive discrimination of benign and malignant breast lesions was examined using area under the receiver operating characteristic curve (AUC). RESULTS: There were 100 malignant and 41 benign lesions (size: median 1.9, range 0.5-10 cm). The multivariate regression model incorporating significant univariate predictors identified tumor enhancement kinetics (P = 0.0003), tumor ADCmean (P < 0.001), and BPE of the contralateral healthy breast (P = 0.0019) as independent predictors for breast cancer diagnosis. Other biomarkers did not reach significance. Combination of the three significant biomarkers achieved an AUC value of 0.98 for breast cancer diagnosis. CONCLUSION: A multiparametric [18F]FDG PET/MRI diagnostic model incorporating both qualitative and quantitative parameters of the tumor and the healthy contralateral tissue aids breast cancer diagnosis.

Multiparametric MRI model with dynamic contrast-enhanced and diffusion-weighted imaging enables breast cancer diagnosis with high accuracy.

BACKGROUND: The MRI Breast Imaging-Reporting and Data System (BI-RADS) lexicon recommends that a breast MRI protocol contain T2 -weighted and dynamic contrast-enhanced (DCE) MRI sequences. The addition of diffusion-weighted imaging (DWI) significantly improves diagnostic accuracy. This study aims to clarify which descriptors from DCE-MRI, DWI, and T2 -weighted imaging are most strongly associated with a breast cancer diagnosis. PURPOSE/HYPOTHESIS: To develop a multiparametric MRI (mpMRI) model for breast cancer diagnosis incorporating American College of Radiology (ACR) BI-RADS recommended descriptors for breast MRI with DCE, T2 -weighted imaging, and DWI with apparent diffusion coefficient (ADC) mapping. STUDY TYPE: Retrospective. SUBJECTS: In all, 188 patients (mean 51.6 years) with 210 breast tumors (136 malignant and 74 benign) who underwent mpMRI from December 2010 to September 2014. FIELD STRENGTH/SEQUENCE: IR inversion recovert DCE-MRI dynamic contrast-enhanced magnetic resonance imaging VIBE Volume-Interpolated-Breathhold-Examination FLASH turbo fast-low-angle-shot TWIST Time-resolved angiography with stochastic Trajectories. ASSESSMENT: Two radiologists in consensus and another radiologist independently evaluated the mpMRI data. Characteristics for mass (n = 182) and nonmass (n = 28) lesions were recorded on DCE and T2 -weighted imaging according to BI-RADS, as well as DWI descriptors. Two separate models were analyzed, using DCE-MRI BI-RADS descriptors, T2 -weighted imagines, and ADCmean as either a continuous or binary form using a previously published ADC cutoff value of ≤1.25 × 10-3 mm2 /sec for differentiation between benign and malignant lesions. Histopathology was the standard of reference. STATISTICAL TESTS: χ2 test, Fisher's exact test, Kruskal-Wallis test, Pearson correlation coefficient, multivariate logistic regression analysis, Hosmer-Lemeshow test of goodness-of-fit, receiver operating characteristics analysis. RESULTS: In Model 1, ADCmean (P = 0.0031), mass margins with DCE (P = 0.0016), and delayed enhancement with DCE (P = 0.0016) were significantly and independently associated with breast cancer diagnosis; Model 2 identified ADCmean (P = 0.0031), mass margins with DCE (P = 0.0012), initial enhancement (P = 0.0422), and delayed enhancement with DCE (P = 0.0065) to be significantly independently associated with breast cancer diagnosis. T2 -weighted imaging variables were not included in the final models. DATA CONCLUSION: mpMRI with DCE-MRI and DWI with ADC mapping enables accurate breast cancer diagnosis. A model using quantitative and qualitative descriptors from DCE-MRI and DWI identifies breast cancer with a high diagnostic accuracy. T2 -weighted imaging does not significantly contribute to breast cancer diagnosis. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:864-874.

Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping as a quantitative imaging biomarker for prediction of immunohistochemical receptor status, proliferation rate, and molecular subtypes of breast cancer.

BACKGROUND: Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping is one of the most useful additional MRI parameters to improve diagnostic accuracy and is now often used in a multiparameric imaging setting for breast tumor detection and characterization. PURPOSE: To evaluate whether different ADC metrics can also be used for prediction of receptor status, proliferation rate, and molecular subtype in invasive breast cancer. STUDY TYPE: Retrospective. SUBJECTS: In all, 107 patients with invasive breast cancer met the inclusion criteria (mean age 57 years, range 32-87) and underwent multiparametric breast MRI. FIELD STRENGTH/SEQUENCE: 3 T, readout-segmented echo planar imaging (rsEPI) with IR fat suppression, dynamic contrast-enhanced (DCE) T1 -weighted imaging, T2 -weighted turbo-spin echo (TSE) with fatsat. ASSESSMENT: Two readers independently drew a region of interest on ADC maps on the whole tumor (WTu), and on its darkest part (DpTu). Minimum, mean, and maximum ADC values of both WTu and DpTu were compared for receptor status, proliferation rate, and molecular subtypes. STATISTICAL TESTS: Wilcoxon rank sum, Mann-Whitney U-tests for associations between radiologic features and histopathology; histogram and q-q plots, Shapiro-Wilk's test to assess normality, concordance correlation coefficient for precision and accuracy; receiver operating characteristics curve analysis. RESULTS: Estrogen receptor (ER) and progesterone receptor (PR) status had significantly different ADC values for both readers. Maximum WTu (P = 0.0004 and 0.0005) and mean WTu (P = 0.0101 and 0.0136) were significantly lower for ER-positive tumors, while PR-positive tumors had significantly lower maximum WTu values (P = 0.0089 and 0.0047). Maximum WTu ADC was the only metric that was significantly different for molecular subtypes for both readers (P = 0.0100 and 0.0132) and enabled differentiation of luminal tumors from nonluminal (P = 0.0068 and 0.0069) with an area under the curve of 0.685 for both readers. DATA CONCLUSION: Maximum WTu ADC values may be used to differentiate luminal from other molecular subtypes of breast cancer. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:836-846.

Engineering of spectator glycocalyx structures to evaluate molecular interactions at crowded cellular boundaries.

In the mucosal epithelium, the cellular glycocalyx can project tens to hundreds of nanometers into the extracellular space, erecting a physical barrier that provides protective functions, mediates the exchange of nutrients and regulates cellular interactions. Little is understood about how the physical properties of the mucosal glycocalyx influence molecular recognition at the cellular boundary. Here, we report the synthesis of PEG-based glycopolymers with tunable glycan composition, which approximate the extended architecture of mucin glycoproteins, and tether them to the plasma membranes of red blood cells (RBC) to construct an artificial mucin brush-like glycocalyx. We evaluated the association of two lectins, ConA and SNA, with their endogenous glycan ligands on the surface of the remodelled cells. The extended glycocalyx provided protection against agglutination of RBCs by both lectins; however, the rate and magnitude of ConA binding were attenuated to a greater degree in the presence of the glycopolymer spectators compared to those measured for SNA. The different sensitivity of ConA and SNA to glycocalyx crowding likely arises from the distinct presentation of their mannoside and sialoside receptors, respectively, within the native RBC glycocalyx.