Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.

Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.

Effectiveness of anterior repositioning splint versus other occlusal splints in the management of temporomandibular joint disc displacement with reduction: A meta-analysis.

BACKGROUND: Disc displacement with reduction (DDwR) is among the common disc disorders of temporomandibular joint (TMJ), which can be managed conservatively by splint therapy. Anterior repositioning splint (ARS) is the most commonly prescribed splint by dental practitioners, but not getting a normal disc-condyle relationship always and other side effects lead to need of comparing with other occlusal splints. This review will help in informed decision-making by clinicians in choosing an appropriate splint type for patients. AIM: The aim is to compare the effectiveness of ARS in the management of DDwR with other occlusal splints for TMJ and muscle pain, TMJ noise, any adverse effects, regaining normal disc-condyle relationship. MATERIALS AND METHODS: We followed published protocol in the International prospective register of systematic reviews. Databases were searched till May 2023 using different search strategies as per the database. Title and abstract screening, followed by full-text screening and data extraction with risk of bias, was done by two independent reviewers in Covidence. Outcomes were reported as risk ratio (RR) or mean difference (MD) for dichotomous or continuous outcomes, respectively, using RevMan 5.4 (Review Manager 5.4) software. We used a random effect model for statistical analysis. Certainty of evidence was assessed using the Grading of Recommendation, Assessment, Development, and Evaluation Guideline Development Tool (GRADEpro GDT) software. RESULTS: A total of 1145 reports were found from a database search. After screening, four studies were included for systematic reviews. Other occlusal splints reported were sagittal vertical extrusion device and mandibular ARS, full hard stabilization splint of canine or centric stabilization type. Data of only two studies could be used for meta-analysis having 30 participants received ARS and 40 received other occlusal splints. We did not find evidence of any difference between ARS and other occlusal splints for TMJ clicking in short term (RR 1.25, 95% confidence interval [CI] 0.91-1.72) but a small difference in favor of other occlusal splint in long term (RR 2.40, 95% CI 1.04-5.55). No evidence of any difference was found between both treatments for TMJ pain in short term (MD-5.68, 95% CI-17.31-5.95) and long term (MD 0.00, 95% CI-2.86-2.86) and muscle pain in short term. The certainty of evidence for comparison of two treatments for different outcomes was of low or very low level. CONCLUSION: Evidence is uncertain that other occlusal splints reduced TMJ clicking slightly in comparison to ARS. For the remaining outcomes, no evidence of any difference was found between the two splints and it may be biased due to selection bias, inadequate blinding of participants, and outcome assessor.

Inhibition of SC4MOL and HSD17B7 shifts cellular sterol composition and promotes oligodendrocyte formation.

While the cholesterol biosynthesis pathway has been extensively studied, recent work has forged new links between inhibition of specific sterol pathway enzymes, accumulation of their unique sterol substrates, and biological areas as diverse as cancer, immunology, and neurodegenerative disease. We recently reported that dozens of small molecules enhance formation of oligodendrocytes, a glial cell type lost in multiple sclerosis, by inhibiting CYP51, Sterol 14-reductase, or EBP and inducing cellular accumulation of their 8,9-unsaturated sterol substrates. Several adjacent pathway enzymes also have 8,9-unsaturated sterol substrates but have not yet been evaluated as potential targets for oligodendrocyte formation or in many other biological contexts, in part due to a lack of available small-molecule probes. Here, we show that genetic suppression of SC4MOL or HSD17B7 increases the formation of oligodendrocytes. Additionally, we have identified and optimized multiple potent new series of SC4MOL and HSD17B7 inhibitors and shown that these small molecules enhance oligodendrocyte formation. SC4MOL inhibitor CW4142 induced accumulation of SC4MOL's sterol substrates in mouse brain and represents an in vivo probe of SC4MOL activity. Mechanistically, the cellular accumulation of these 8,9-unsaturated sterols represents a central driver of enhanced oligodendrocyte formation, as exogenous addition of purified SC4MOL and HSD17B7 substrates but not their 8,9-saturated analogs promotes OPC differentiation. Our work validates SC4MOL and HSD17B7 as novel targets for promoting oligodendrocyte formation, underlines a broad role for 8,9-unsaturated sterols as enhancers of oligodendrocyte formation, and establishes the first high-quality small molecules targeting SC4MOL and HSD17B7 as novel tools for probing diverse areas of biology.

Salpingovesical fistula mimicking an enterovaginal fistula.

Fallopian tube fistula with the bladder can mimic an enterovaginal fistula. A 34-year-old woman presented with continuous urinary incontinence after hysterectomy. A cystogram confirmed a vesicovaginal fistula and a possible additional intestinal communication. Further imaging, however, ruled out an enterovaginal fistula and diagnosed a fallopian tube prolapse with salpingovesicovaginal fistula. This case demonstrates the importance of multiple imaging modalities in identifying and clearly delineating the anatomy of gynecologic fistulous connections. The case illustrates the fact that while salpingovesical fistula is a rare complication of hysterectomy, it is an important consideration in one's differential diagnosis.

Computer-Aided Detection AI Reduces Interreader Variability in Grading Hip Abnormalities With MRI.

BACKGROUND: Accurate interpretation of hip MRI is time-intensive and difficult, prone to inter- and intrareviewer variability, and lacks a universally accepted grading scale to evaluate morphological abnormalities. PURPOSE: To 1) develop and evaluate a deep-learning-based model for binary classification of hip osteoarthritis (OA) morphological abnormalities on MR images, and 2) develop an artificial intelligence (AI)-based assist tool to find if using the model predictions improves interreader agreement in hip grading. STUDY TYPE: Retrospective study aimed to evaluate a technical development. POPULATION: A total of 764 MRI volumes (364 patients) obtained from two studies (242 patients from LASEM [FORCe] and 122 patients from UCSF), split into a 65-25-10% train, validation, test set for network training. FIELD STRENGTH/SEQUENCE: 3T MRI, 2D T2 FSE, PD SPAIR. ASSESSMENT: Automatic binary classification of cartilage lesions, bone marrow edema-like lesions, and subchondral cyst-like lesions using the MRNet, interreader agreement before and after using network predictions. STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, area under curve (AUC), specificity and sensitivity, and balanced accuracy. RESULTS: For cartilage lesions, bone marrow edema-like lesions and subchondral cyst-like lesions the AUCs were: 0.80 (95% confidence interval [CI] 0.65, 0.95), 0.84 (95% CI 0.67, 1.00), and 0.77 (95% CI 0.66, 0.85), respectively. The sensitivity and specificity of the radiologist for binary classification were: 0.79 (95% CI 0.65, 0.93) and 0.80 (95% CI 0.59, 1.02), 0.40 (95% CI -0.02, 0.83) and 0.72 (95% CI 0.59, 0.86), 0.75 (95% CI 0.45, 1.05) and 0.88 (95% CI 0.77, 0.98). The interreader balanced accuracy increased from 53%, 71% and 56% to 60%, 73% and 68% after using the network predictions and saliency maps. DATA CONCLUSION: We have shown that a deep-learning approach achieved high performance in clinical classification tasks on hip MR images, and that using the predictions from the deep-learning model improved the interreader agreement in all pathologies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:1163-1172.

Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer.

IMPORTANCE: Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC). OBJECTIVE: To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance. DESIGN, SETTING, AND PARTICIPANTS: In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction-based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years. MAIN OUTCOMES AND MEASURES: Outcomes were ctDNA measurement, clinical recurrence, and recurrence-free survival. RESULTS: A total of 130 patients with stages I to III CRC (mean [SD] age, 67.9 [10.1] years; 74 [56.9%] male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients (88.5%). After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients (hazard ratio [HR], 7.2; 95% CI, 2.7-19.0; P < .001). Similarly, shortly after ACT ctDNA-positive patients were 17 times (HR, 17.5; 95% CI, 5.4-56.5; P < .001) more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 43.5; 95% CI, 9.8-193.5 P < .001). In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples. CONCLUSIONS AND RELEVANCE: Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma.

PURPOSE: Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy. PATIENTS AND METHODS: We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses. RESULTS: Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence (P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging (P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods. CONCLUSION: ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.

Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence.

PURPOSE: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer. EXPERIMENTAL DESIGN: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X). RESULTS: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling. CONCLUSIONS: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.

Detection of Lumbar Spine Osseous Metastases Using Dual-Energy CT: Phantom Results and Preliminary Clinical Validation.

OBJECTIVE: The purpose of this study was to evaluate the sensitivity, tumor conspicuity, and image quality of different material decomposition images of phantoms and patients with nearly isodense bone metastases using rapid-kilovoltage-switching dual-energy CT (DECT). MATERIALS AND METHODS: Fifty-one semianthropomorphic lumbar spine phantoms embedded with 75 simulated tumors were scanned without and with outer torso-attenuating encasement under the same scan settings. Two radiologists independently reviewed the 70-keV virtual monochromatic and material decomposition images (hydroxyapatite-water, water-hydroxyapatite, cortical bone-water, water-cortical bone). The sensitivity of tumor detection, tumor conspicuity (on a 3-point scale), and image quality (on a 3-point scale) were recorded by two independent readers. McNemar and Wilcoxon signed rank tests were used to compare results between the image reconstructions. Six clinical abdominopelvic DECT scans (three men, three women; mean age, 52 years) with nine nearly isodense lumbar spine tumors missed in the clinical report but confirmed on other scans were also evaluated. RESULTS: The hydroxyapatite-water material decomposition algorithm showed improved sensitivity for isodense lesion detection (without torso phantom encasement, 94% vs 82%, p = 0.031; with torso phantom encasement, 38% vs 18%, p = 0.013), and higher tumor conspicuity scores (p < 0.0001) compared with 70-keV virtual monoenergetic images. Artifacts were more prevalent with all material decomposition images than with 70-keV virtual monoenergetic images. Similar results were seen in the patient study. CONCLUSION: Dual-energy CT with hydroxyapatite-water material decomposition may improve the detection of bone marrow metastases, especially for subtle isodense tumors. Further study in prospective clinical scans is warranted.

MRI of lesser metatarsophalangeal joint plantar plate tears and associated adjacent interspace lesions.

OBJECTIVE: To identify the variety of second and third intermetatarsal space (IS) lesions that may coexist with and without adjacent metatarsophalangeal joint (MTP) plantar plate (PP) tears. MATERIALS AND METHODS: One hundred forefoot MRIs in 96 patients with metatarsalgia obtained between 30 September 2011 and 21 July 2012 using 1.5- or 3-T MRI were retrospectively reviewed in consensus by two MSK radiologists and one podiatrist (DPM). MRI was evaluated for second and third MTP PP tear and the presence/nature of second and third IS lesions. Second and third IS neuromas were measured in transverse (trans) dimension. RESULTS: A total of 40 PP tears were identified: 36 at the second and 4 at the third MTP. Second MTP PP tear was identified in 33% of females and 40.5% of males. In the 63 female feet there were 21 second MTP PP tears, all of which also had second IS lesions: pericapsular fibrosis (16), bursitis (4), and ganglion (1). In the 37 male feet there were 15 second MTP PP tears, 14 of which had second IS lesions: pericapsular fibrosis (8), bursitis (5), and ganglion (1). There was no definite second IS neuroma adjacent to any second MTP PP tear. In females without PP tear, there were 24 second (3 mm trans average) and 43 third IS neuromas (4.1 mm trans average). In males without PP tear, there were 9 second (3.4 mm trans average) and 16 third IS neuromas (4.1 mm trans average). CONCLUSIONS: MTP PP tears occurred in 40% of our cases, 90% of which occurred at the second MTP. Almost all coexisted with non-neuromatous second IS lesions.

Ultrasound for differentiation between perforated and nonperforated appendicitis in pediatric patients.

OBJECTIVE: Acute appendicitis is the most common condition requiring emergency surgery in children. Differentiation of perforated from nonperforated appendicitis is important because perforated appendicitis may initially be managed conservatively whereas nonperforated appendicitis requires immediate surgical intervention. CT has been proved effective in identifying appendiceal perforation. The purpose of this study was to determine whether perforated and nonperforated appendicitis in children can be similarly differentiated with ultrasound. MATERIALS AND METHODS: This retrospective study included 161 consecutively registered children from two centers who had acute appendicitis and had undergone ultra-sound and appendectomy. Ultrasound images were reviewed for appendiceal size, appearance of the appendiceal wall, changes in periappendiceal fat, and presence of free fluid, abscess, or appendicolith. The surgical report served as the reference standard for determining whether perforation was present. The specificity and sensitivity of each ultrasound finding were determined, and binary models were generated. RESULTS: The patients included were 94 boys and 67 girls (age range, 1-20 years; mean, 11 ± 4.4 [SD] years) The appendiceal perforation rate was significantly higher in children younger than 8 years (62.5%) compared with older children (29.5%). Sonographic findings associated with perforation included abscess (sensitivity, 36.2%; specificity, 99%), loss of the echogenic submucosal layer of the appendix in a child younger than 8 years (sensitivity, 100%; specificity, 72.7%), and presence of an appendicolith in a child younger than 8 years (sensitivity, 68.4%; specificity, 91.7%). CONCLUSION: Ultrasound is effective for differentiation of perforated from nonperforated appendicitis in children.

Iodine quantification with dual-energy CT: phantom study and preliminary experience with renal masses.

OBJECTIVE: The purpose of this study was to validate the utility of dual-source dual-energy MDCT in quantifying iodine concentration in a phantom and in renal masses. MATERIALS AND METHODS: A series of tubes containing solutions of varying iodine concentration were imaged with dual-source dual-energy MDCT. Iodine concentration was calculated and compared with known iodine concentration. Single-phase contrast-enhanced dual-source dual-energy MDCT data on 15 patients with renal lesions then were assessed independently by two readers. Dual-energy postprocessing was used to generate iodine-only images. Regions of interest were placed on the iodine image over the lesion and, as a reference, over the aorta, for recording of iodine concentration in the lesion and in the aorta. Another radiologist determined lesion enhancement by comparing truly unenhanced with contrast-enhanced images. Mixed-model analysis of variance based on ranks was used to compare lesion types (simple cyst, hemorrhagic cyst, enhancing mass) in terms of lesion iodine concentration and lesion-to-aorta iodine ratio. RESULTS: In the phantom study, there was excellent correlation between calculated and true iodine concentration (R(2) = 0.998, p < 0.0001). In the patient study, 13 nonenhancing (10 simple and three hyperdense cysts) and eight enhancing renal masses were evaluated in 15 patients. The lesion iodine concentration and lesion-to-aorta iodine ratio in enhancing masses were significantly higher than in hyperdense and simple cysts (p < 0.0001). CONCLUSION: Iodine quantification with dual-source dual-energy MDCT is accurate in a phantom and can be used to determine the presence and concentration of iodine in a renal lesion. Characterization of renal masses may be possible with a single dual-source dual-energy MDCT acquisition without unenhanced images or reliance on a change in attenuation measurements.

Static and dynamic quenching of Ru(II) polypyridyl excited states by iodide.

The metal-to-ligand charge-transfer (MLCT) excited states of Ru(bpy)(2)(deeb)(PF(6))(2), where bpy is 2,2-bipyridine and deeb is 4,4'-(CO(2)CH(2)CH(3))(2)-2,2'-bipyridine, in dichloromethane were found to be efficiently quenched by iodide at room temperature. The ionic strength dependence of the UV-visible absorption spectra gave evidence for ion pairing. Iodide was found to quench the excited states by static and dynamic mechanisms. Stern-Volmer and Benesi-Hildebrand analysis of the spectral data provided a self-consistent estimate of the iodide-Ru(bpy)(2)(deeb)(2+) adduct in dichloromethane, K = 59 700 M(-1). Transient absorption studies clearly demonstrated an electron-transfer quenching mechanism with transient formation of I(2)(*)(-) in high yield, phi = 0.25 for 355 or 532 nm excitation. For Ru(bpy)(2)(deeb)(PF(6))(2) in acetonitrile, similar behavior could be observed at higher iodide concentrations than that required in dichloromethane. The parent Ru(bpy)(3)(2+) compound also ion pairs with iodide in CH(2)Cl(2), and light excitation gave a higher I(2)(*)(-) yield, phi = 0.50. X-ray crystallographic, IR, and Raman data gave evidence for interactions between iodide and the coordinated deeb ligand in the solid state.