Radiologic Progression of Interstitial Lung Abnormalities following Surgical Resection in Patients with Lung Cancer.

In this study, we aimed to assess the prevalence of interstitial lung abnormalities (ILAs) and investigate the rates and risk factors associated with radiologic ILA progression among patients with lung cancer following surgical resection. Patients who underwent surgical resection for lung cancer at our institution from January 2015 to December 2020 were retrospectively evaluated and grouped according to their ILA status as having no ILAs, equivocal ILAs, or ILAs. Progression was determined by simultaneously reviewing the baseline and corresponding follow-up computed tomography (CT) scans. Among 346 patients (median age: 67 (interquartile range: 60-74) years, 204 (59.0%) men), 22 (6.4%) had equivocal ILAs, and 33 (9.5%) had ILAs detected upon baseline CT. Notably, six patients (6/291; 2.1%) without ILAs upon baseline CT later developed ILAs, and 50% (11/22) of those with equivocal ILAs exhibited progression. Furthermore, 75.8% (25/33) of patients with ILAs upon baseline CT exhibited ILA progression (76.9% and 71.4% with fibrotic and non-fibrotic ILAs, respectively). Multivariate analysis revealed that ILA status was a significant risk factor for ILA progression. ILAs and equivocal ILAs were associated with radiologic ILA progression after surgical resection in patients with lung cancer. Hence, early ILA detection can significantly affect clinical outcomes.

Diagnostic Accuracy and Complication of Computed Tomography (CT)-Guided Percutaneous Transthoracic Lung Biopsy in Patients 80 Years and Older.

This research evaluated the diagnostic accuracy and complication rate of computed tomography (CT)-guided percutaneous transthoracic lung biopsy (PTNB) in patients 80 years and older. The study sought to identify risk factors for diagnostic failures or complications of PTNBs. We examined 247 CT-guided PTNBs performed from January 2017 through December 2020, noting patient demographics, lesion or procedure types, pathology reports, and other procedure-related complications. Study groups were divided into two: one with patients aged 80 years and older (Group 1) and the other with patients aged 60 to 80 years (Group 2). The research first determined each groups' diagnostic accuracy, sensitivity, specificity, diagnostic failure rate, and complication rate and then evaluated the risk factors for diagnostic failures and complications. The diagnostic accuracy, sensitivity, specificity, and diagnostic failure rates were 95.6%, 94.9%, 100%, and 18.9%, respectively, in Group 1. The overall and major complication rates in Group 1 were 29.6% and 3.7%, respectively. Lesion size was the only risk factor for diagnostic failure (adjusted odds ratio [OR], 0.46; 95% confidence interval [CI], 0.24-0.90). There was no significant risk factor for complications in Group 1. CT-guided PTNBs in patients 80 years and older indicate comparable diagnostic accuracy and complication rates.

Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-ß-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3-6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.

Accuracy and complications of percutaneous transthoracic needle lung biopsy for the diagnosis of malignancy in patients with idiopathic pulmonary fibrosis.

OBJECTIVES: To determine the accuracy of CT-guided percutaneous transthoracic needle lung biopsy (PTNB) for the diagnosis of malignancy and the associated complication rates in patients with idiopathic pulmonary fibrosis (IPF). METHODS: This retrospective study included 91 CT-guided PTNBs performed in 80 patients with IPF from April 2003 through December 2016. Data regarding patients, target lesions, procedures, complications, and pathological reports were collected, and the final diagnosis was made. The diagnostic accuracy, sensitivity, specificity, percentage of nondiagnostic results, and complication rates were determined. Multivariable logistic regression analyses were performed to identify risk factors for nondiagnostic results and major complications. RESULTS: Three biopsies (technical failure [n = 2] and undetermined final diagnosis [n = 1]) were excluded from the diagnostic accuracy calculation. The diagnostic accuracy, sensitivity, and specificity were 89% (78/88), 90% (62/69), and 84% (16/19), respectively. The percentage of nondiagnostic results was 34% (30/88). Lesion size ≤ 3 cm (odds ratio [OR], 8.8; 95% confidence interval [CI], 2.5-31.2; p = 0.001) and needle tip placement outside the target lesion (OR, 13.7; 95% CI, 1.4-132.2; p = 0.02) were risk factors for nondiagnostic results. The overall and major complication rates were 51% (46/91) and 12% (11/91), respectively. The presence of honeycombing along the path of the needle (OR, 11.2; 95% CI, 1.4-89.1; p = 0.02) was an independent risk factor for major complications. CONCLUSIONS: CT-guided PTNB shows a relatively reasonable accuracy in diagnosing malignancy in patients with IPF. The complication rate may be high, especially when the needle passes through honeycomb lesions. KEY POINTS: • In patients with idiopathic pulmonary fibrosis (IPF), CT-guided percutaneous transthoracic needle lung biopsy (PTNB) showed a relatively reasonable accuracy for the diagnosis of malignancy. • Target lesion size ≤ 3 cm and biopsy needle tip placement outside the target lesion were risk factors for nondiagnostic results of CT-guided PTNB. • The complication rate may be high, especially in cases where the biopsy needle passes through honeycomb lesions.

Efficient distribution of oral vaccines examined by infrared triggered camera for advancing the control of raccoon dog rabies in South Korea.

The field distribution of the oral rabies vaccine is effective in controlling the spread of rabies. The present study aimed to investigate efficient distribution locations based on the environment, contact rate, and consumption by target wildlife species in South Korea. The target species (Korean raccoon dogs, domestic dogs, and feral cats) accounted for 945 contacts (52.2%), in total 1,808 contacts. There were 863 (47.8%) contacts by non-target species. Raccoon dogs, a main reservoir of rabies in South Korea, had the highest contact rate (34.1%) among all species. The contact rate by target species was highest at riparian sites and bushy mountainous vegetation, where raccoon dogs are abundant. There was remarkable contact by raccoon dogs in mountainous areas below 150 m with bushy vegetation. Our results indicate that these locations are efficient areas for vaccine distribution, especially targeting the raccoon dog. Vaccines were continuously contacted with intervals ranging from one hour to one day. Vaccines at 94.4% of the distribution points were completely consumed within two weeks. The mean consumption rate was 95.2 ± 1.93% during the overall study period. These findings suggest that the oral rabies vaccine attracts wildlife including domestic dogs and feral cats. Our results suggest that low sections of mountainous areas with bushy vegetation and/or neighboring riparian areas are rich in target wildlife species (especially raccoon dogs) and are efficient locations for vaccine distribution to control rabies in South Korea.

Deep Learning-based Automatic Detection Algorithm for Reducing Overlooked Lung Cancers on Chest Radiographs.

Background It is uncertain whether a deep learning-based automatic detection algorithm (DLAD) for identifying malignant nodules on chest radiographs will help diagnose lung cancers. Purpose To evaluate the efficacy of using a DLAD in observer performance for the detection of lung cancers on chest radiographs. Materials and Methods Among patients diagnosed with lung cancers between January 2010 and December 2014, 117 patients (median age, 69 years; interquartile range [IQR], 64-74 years; 57 women) were retrospectively identified in whom lung cancers were visible on previous chest radiographs. For the healthy control group, 234 patients (median age, 58 years; IQR, 48-68 years; 123 women) with normal chest radiographs were randomly selected. Nine observers reviewed each chest radiograph, with and without a DLAD. They detected potential lung cancers and determined whether they would recommend chest CT for follow-up. Observer performance was compared with use of the area under the alternative free-response receiver operating characteristic curve (AUC), sensitivity, and rates of chest CT recommendation. Results In total, 105 of the 117 patients had lung cancers that were overlooked on their original radiographs. The average AUC for all observers significantly rose from 0.67 (95% confidence interval [CI]: 0.62, 0.72) without a DLAD to 0.76 (95% CI: 0.71, 0.81) with a DLAD (P < .001). With a DLAD, observers detected more overlooked lung cancers (average sensitivity, 53% [56 of 105 patients] with a DLAD vs 40% [42 of 105 patients] without a DLAD) (P < .001) and recommended chest CT for more patients (62% [66 of 105 patients] with a DLAD vs 47% [49 of 105 patients] without a DLAD) (P < .001). In the healthy control group, no difference existed in the rate of chest CT recommendation (10% [23 of 234 patients] without a DLAD and 8% [20 of 234 patients] with a DLAD) (P = .13). Conclusion Using a deep learning-based automatic detection algorithm may help observers reduce the number of overlooked lung cancers on chest radiographs, without a proportional increase in the number of follow-up chest CT examinations. © RSNA, 2020 Online supplemental material is available for this article.

Usefulness of CT-Guided Percutaneous Transthoracic Needle Lung Biopsies in Patients with Suspected Pulmonary Infection.

OBJECTIVE: This study aimed to evaluate the clinical benefits and risks of CT-guided percutaneous transthoracic needle lung biopsies (PTNBs) in patients with a suspected pulmonary infection. MATERIALS AND METHODS: This study included 351 CT-guided PTNBs performed in 342 patients (mean age, 58.9 years [range, 17-91 years]) with suspected pulmonary infection from January 2010 to December 2016. The proportion of biopsies that revealed the causative organism for pulmonary infection and that influenced patient's treatment were measured. Multivariate analyses were performed to identify factors associated with PTNB that revealed the causative organism or affected the treatment. Finally, the complication rate was measured. RESULTS: CT-guided PTNB revealed the causative organism in 32.5% of biopsies (114/351). The presence of necrotic components in the lesion (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.1-2.7; p = 0.028), suspected pulmonary tuberculosis (OR, 2.0; 95% CI, 1.2-3.5; p = 0.010), and fine needle aspiration (OR, 2.5; 95% CI, 1.1-5.8; p = 0.037) were factors associated with biopsies that revealed the causative organism. PTNB influenced patient's treatment in 40.7% (143/351) of biopsies. The absence of leukocytosis (OR, 1.9; 95% CI, 1.0-3.7; p = 0.049), presence of a necrotic component in the lesion (OR, 2.4; 95% CI, 1.5-3.8; p < 0.001), and suspected tuberculosis (OR, 1.7; 95% CI, 1.0-2.8; p = 0.040) were factors associated with biopsies that influenced the treatment. The overall complication rate of PTNB was 19% (65/351). CONCLUSION: In patients with suspected pulmonary infection, approximately 30-40% of CT-guided PTNBs revealed the causative organism or affected the treatment. The complication rate of PTNB for suspected pulmonary infection was relatively low.

Low-Dose Abdominal CT Using a Deep Learning-Based Denoising Algorithm: A Comparison with CT Reconstructed with Filtered Back Projection or Iterative Reconstruction Algorithm.

OBJECTIVE: To compare the image quality of low-dose (LD) computed tomography (CT) obtained using a deep learning-based denoising algorithm (DLA) with LD CT images reconstructed with a filtered back projection (FBP) and advanced modeled iterative reconstruction (ADMIRE). MATERIALS AND METHODS: One hundred routine-dose (RD) abdominal CT studies reconstructed using FBP were used to train the DLA. Simulated CT images were made at dose levels of 13%, 25%, and 50% of the RD (DLA-1, -2, and -3) and reconstructed using FBP. We trained DLAs using the simulated CT images as input data and the RD CT images as ground truth. To test the DLA, the American College of Radiology CT phantom was used together with 18 patients who underwent abdominal LD CT. LD CT images of the phantom and patients were processed using FBP, ADMIRE, and DLAs (LD-FBP, LD-ADMIRE, and LD-DLA images, respectively). To compare the image quality, we measured the noise power spectrum and modulation transfer function (MTF) of phantom images. For patient data, we measured the mean image noise and performed qualitative image analysis. We evaluated the presence of additional artifacts in the LD-DLA images. RESULTS: LD-DLAs achieved lower noise levels than LD-FBP and LD-ADMIRE for both phantom and patient data (all p < 0.001). LD-DLAs trained with a lower radiation dose showed less image noise. However, the MTFs of the LD-DLAs were lower than those of LD-ADMIRE and LD-FBP (all p < 0.001) and decreased with decreasing training image dose. In the qualitative image analysis, the overall image quality of LD-DLAs was best for DLA-3 (50% simulated radiation dose) and not significantly different from LD-ADMIRE. There were no additional artifacts in LD-DLA images. CONCLUSION: DLAs achieved less noise than FBP and ADMIRE in LD CT images, but did not maintain spatial resolution. The DLA trained with 50% simulated radiation dose showed the best overall image quality.

Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging.

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease with no cure. Although IPF is widely regarded as a disease of aging, the cellular mechanisms that contribute to this age-associated predilection remain elusive. In this study, we sought to evaluate the consequences of senescence on myofibroblast cell fate and fibrotic responses to lung injury in the context of aging. We demonstrated that nonsenescent lung myofibroblasts maintained the capacity for dedifferentiation, whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation. We previously demonstrated that the transcription factor MyoD acts as a critical switch in the differentiation and dedifferentiation of myofibroblasts. Here, we demonstrate that decreased levels of MyoD preceded myofibroblast dedifferentiation and apoptosis susceptibility in nonsenescent cells, whereas MyoD expression remained elevated in senescent/IPF myofibroblasts, which failed to undergo dedifferentiation and demonstrated resistance to apoptosis. Genetic strategies to silence MyoD restored the susceptibility of IPF myofibroblasts to undergo apoptosis and led to a partial reversal of age-associated persistent fibrosis in vivo. The capacity for myofibroblast dedifferentiation and subsequent apoptosis may be critical for normal physiologic responses to tissue injury, whereas restricted dedifferentiation and apoptosis resistance in senescent cells may underlie the progressive nature of age-associated human fibrotic disorders. These studies support the concept that senescence may promote profibrotic effects via impaired myofibroblast dedifferentiation and apoptosis resistance, which contributes to myofibroblast accumulation and ultimately persistent fibrosis in aging.

Improved repeatability of subsolid nodule measurement in low-dose lung screening with monoenergetic images: a phantom study.

BACKGROUND: To investigate whether monoenergetic images captured with dual-layer spectral computed tomography (CT) can improve the repeatability of subsolid nodule measurement, and whether this approach can further reduce the radiation dose of CT while maintaining its measurement repeatability. METHODS: An anthropomorphic phantom with simulated subsolid nodules at three different levels was repeatedly scanned with both conventional single-energy CT and dual-layer spectral CT. A proxy for the measurement repeatability in the National Lung Screening Trial (proxy for NLST) was calculated with the typical CT protocol used in NLST. Using the dual-layer spectral CT, monoenergetic images of 40 to 110 keV, with an interval of 10 keV, were generated. The average diameter and volume of a total of 15,120 nodules in 840 CT images were measured by using a commercially-available computer-aided detection (CAD) system. The repeatability coefficient (RC), %RC, and 95% confidence intervals (CIs) of each image set were calculated and compared. RESULTS: At the same tube voltage and tube current-time product, monoenergetic images resulted in significantly lower RC than the proxy for NLST, indicating that measurement repeatability was enhanced. When the radiation dose was lowered by 30% or 55%, monoenergetic images showed significantly lower RC at high-energy keV than the proxy for NLST. The estimated measurement repeatability from monoenergetic images with 30% or 55% lower radiation dose was comparable to the repeatability from conventional single-energy CT images with standard radiation dose and iterative reconstruction. CONCLUSIONS: Monoenergetic images captured by using dual-layer spectral CT can improve the repeatability of subsolid nodule measurement. The use of monoenergetic images would allow lung cancer screening with a lower radiation dose, while maintaining comparable measurement repeatability.

Clinical significance of evaluating coronary atherosclerosis in adult patients with hypertrophic cardiomyopathy who have chest pain.

OBJECTIVE: Chest pain is a common symptom in patients with hypertrophic cardiomyopathy (HCM), causing difficulty determining whether there is coexistent coronary artery disease (CAD). We investigated whether coronary computed tomography angiography (CCTA) can assess the prevalence and clinical significance of CAD in adult patients with HCM showing chest pain through longitudinal follow-up. METHODS: In 238 adult patients with HCM, who underwent CCTA for chest pain, we analyzed the degree of stenosis and adverse plaque characteristics (APCs) as CCTA variables. Three prediction models for adverse cardiovascular events (ACEs: all-cause mortality, myocardial infarction, unstable angina, heart failure, implantable cardioverter-defibrillator implantation, and stroke) were assessed using the combination of clinical risk factors, echocardiographic parameters, and CCTA variables. RESULTS: The prevalence of obstructive CAD (≥ 50% in luminal stenosis) and APC was 14.7% and 18.9%, respectively. During the follow-up period (median, 37 months; range, 2-108 months), there were 31 occurrences of ACEs (13.0%). Using multivariate Cox regression analysis, age, atrial fibrillation, low ejection fraction, obstructive CAD, and APCs were associated with ACEs (all p < 0.05). Among the prediction models for ACEs, the area under the curve (AUC) was higher (AUC = 0.92) when CCTA variables were added to the clinical (AUC = 0.84) and echocardiographic factors (AUC = 0.88) (p < 0.001). CONCLUSIONS: Using CCTA, about 20% of symptomatic HCM patients were associated with clinically significant atherosclerosis. Adding these CCTA variables to the clinical and echocardiographic variables may increase the predictions of ACEs; therefore, evaluating coronary atherosclerosis using CCTA may be helpful for symptomatic HCM patients. KEY POINTS: • Chest pain in adult patients with hypertrophic cardiomyopathy (HCM) remains challenging to distinguish from coronary artery disease. • Coronary computed tomography angiography (CCTA) can assess the severity and characteristics of coronary atherosclerosis in symptomatic HCM patients. • Adding CCTA variables to clinical and echocardiographic factors may increase the predictions of adverse cardiac events in HCM patients, and thus evaluating coronary atherosclerosis using CCTA may be helpful for HCM patients with chest pain.

Predictors of Invasive Breast Cancer in Patients With Ductal Carcinoma In Situ in Ultrasound-Guided Core Needle Biopsy.

OBJECTIVES: To determine predictors of invasiveness of lesions with US-guided biopsy-confirmed ductal carcinoma in situ (DCIS), focusing on US features, including shear wave elastography (SWE). METHODS: From January 2015 to September 2016, a total of 80 lesions with US-guided biopsy-confirmed DCIS were detected in patients who underwent preoperative mammography, B-mode US, and SWE. Data were retrospectively reviewed from clinical records, pathologic reports, and imaging assessments. Imaging data included mammographic findings, B-mode US findings based on the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS), and the mean and maximum elasticity values on SWE. The final BI-RADS assessment, including the degree of elasticity of the mass, was evaluated. Continuous variables were examined by an independent t test, and categorical variables were examined by the Fisher exact test. The independent factors for predicting a histologic upgrade were evaluated by a multivariate logistic regression analysis. RESULTS: Among the 80 lesions, 27 (33.8%) showed an invasive component after surgical excision. None of the BI-RADS US descriptors, which include shape, orientation, margin, and echogenicity, showed a significant correlation with the rate of a histologic upgrade to invasive cancer. However, the BI-RADS assessment category (P = .015) and nuclear grade (P = .005) were significantly correlated with invasiveness of the mass. The maximum stiffness value was lower in the pure DCIS group (119.04 vs 85.33 kPa; P = .041). CONCLUSIONS: The BI-RADS category based on US findings, maximum stiffness value on SWE, and nuclear grade of DCIS are predictive of invasive components in DCIS.

Relationship between sociability toward humans and physiological stress in dogs.

Sociability is an essential trait for dogs to successfully interact with humans. In this study, the relationship between sociability and physiological stress was examined. Additionally, whether differences exist between companion dogs (C group) and shelter dogs (S group) was examined. Overall, healthy 37 dogs (C group=21 and S group=16) were examined. After 5 min of walking, the dog and the owner (or the chief manager) rested freely in the experimental location for 5 min. The behavioral test with 6 categories was conducted to evaluate sociability over 4 min. The establishment of two groups (H group=dogs with high sociability; L group=dogs with low sociability) was supported by the statistical results of the behavioral tests. Saliva was collected before (P1) and after the test period (P2), and salivary cortisol levels were determined and statistically analyzed. The cortisol concentrations at P2 and the differences in concentrations between P1 and P2 (P2-P1) in the groups with high sociability were significantly lower than those in the groups with low sociability. These results may demonstrate that sociable dogs adapt more comfortably to strangers and unfamiliar situations. Meanwhile, there were significant differences in hormonal results between the C and S groups. For this reason, their sociability should be evaluated using behavioral and physiological assessments before re-adoption to ensure their successful adaptation.

Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury.

Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population, with both higher incidence and mortality. The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in the context of aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 mo) and aged (18 mo) mice using a two-hit preclinical model. Compared with young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated albumin influx and levels of bronchoalveolar lavage (BAL) cells (neutrophils) and protein. Aged/injured mice also demonstrated elevated levels of reactive oxygen species (ROS) in the BAL, which was associated with upregulation of the ROS-generating enzyme, Nox4. We evaluated the role of aging in human lung EC barrier regulation utilizing a cellular model of replicative senescence. Senescent EC populations were defined by increases in ß-galactosidase activity and p16 levels. In response to lipopolysaccharide (LPS) challenge, senescent ECs demonstrate exacerbated permeability responses compared with control "young" ECs. LPS challenge led to a rapid induction of Nox4 expression in both control and senescent ECs, which was posttranslationally mediated via the proteasome/ubiquitin system. However, senescent ECs demonstrated deficient Nox4 ubiquitination, resulting in sustained expression of Nox4 and alterations in cellular redox homeostasis. Pharmacological inhibition of Nox4 in senescent ECs reduced LPS-induced alterations in permeability. These studies provide insight into the roles of Nox4/senescence in EC barrier responses and offer a mechanistic link to the increased incidence and mortality of ARDS associated with aging.

Evaluation of effects of olfactory and auditory stimulation on separation anxiety by salivary cortisol measurement in dogs.

Separation anxiety (SA) is a serious behavioral problem in dogs. In this study, salivary cortisol was studied to determine if the owner's odor or voice could reduce SA in dogs. Twenty-eight dogs with SA were divided into three groups: group 1 (control), group 2 (with owner's clothes during the separation period; SP) and group 3 (a recording of the owner's voice was played during SP). The dog's saliva was collected after the owner and their dog were in the experimental room for 5 min (PRE). The dog was then separated from the owner for 20 min and saliva collected four times at intervals of 5 min (SP1-4). Finally, the owner was allowed back into the room to calm the dog for 5 min, after which saliva was collected (POST). Evaluation of salivary cortisol concentrations by ELISA revealed that the ratios of SP1 concentration to PRE or POST concentrations were significantly higher in group 1 than in group 2 or 3. Additionally, the concentrations of SP1-PRE and SP1-POST among groups differed significantly. These findings indicate that the owner's odor or voice may be helpful to managing stress in dogs with SA.

Acute benign vertebral compression fractures: "see-through sign" on contrast-enhanced MR images.

PURPOSE: To retrospectively evaluate the diagnostic role of the contrast-enhanced MRI (CE-MRI) for differentiation between benign VCFs and malignant VCFs focusing on the internal transparent trabecular bone on CE-MRI (the "see-through sign"). MATERIALS AND METHODS: The institutional review board approved this study and informed consent was waived due to the retrospective nature of the study. From January 2012 to December 2013, all 149 consecutive benign or malignant VCF patients were enrolled for consideration in this study from a CE-MRI database. In the first analysis, four radiologists independently evaluated the presence or absence of the see-through sign. The see-through sign was defined as internal transparent trabecular bone morphology on CE-MRI. The intraclass correlation coefficient (ICC), percentage agreement, and Fleiss's kappa statistics were obtained. RESULTS: Fifty-seven patients (M:F = 27:30; mean age, 63 years; age range, 20-88 years) who diagnosed as acute benign (n = 24) and malignant (n = 33) VCFs were finally included for the analysis. The results of all readers showed that the see-through sign was associated with acute benign VCFs (p < 0.05). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of the see-through sign ranged from 75-96, 70-88, 66-85, 81-97 %, respectively. The inter-observer reliability of the see-through sign was sufficient with ICC = 0.847, percentage agreement = 78.9, and κ = 0.578. CONCLUSION: The see-through sign on CE-MRI is featured in acute benign VCFs, and it can be a useful finding to differentiate between benign and malignant VCFs.

Selective repression of RET proto-oncogene in medullary thyroid carcinoma by a natural alkaloid berberine.

BACKGROUND: The gain-of-function mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase, is strongly associated with the development of several medullary thyroid carcinomas (MTCs). Thus, the RET protein has been explored as an excellent target for progressive and advanced MTC. In this study we have demonstrated a therapeutic strategy for MTC by suppressing the transcription of RET proto-oncogene though the stabilization of G-quadruplex structure formed on the promoter region of this gene using a natural product berberine. METHODS: Medullary thyroid carcinoma (MTC) TT cell line has been used to evaluate the effects of berberine on RET expression and its downstream signaling pathways. The specificity of berberine was demonstrated by using the papillary thyroid carcinoma TPC1 cell line, which lacks the G-quadruplex forming sequence on the RET promoter region due to chromosomal rearrangement. RESULTS: Berberine suppressed the RET expression by more than 90 % in MTC TT cells at a concentration of 2.5 µg/ml with minimal effect on the TPC1 cells. Canadine, which is a structural analogue of berberine, showed little interaction with RET G-quadruplex and also had no effect on RET expression in MTC TT cells. The down-regulation of RET with berberine further inhibited the cell proliferation through cell cycle arrest and activation of apoptosis in TT cells, which was confirmed by a 2-fold increase in the caspase-3 activity and the down-regulation of cell-cycle regulatory proteins. CONCLUSION: Our data strongly suggest that the G-quadruplex forming region and the stabilization of this structure play a critical role in mediating the repressive effect of berberine on RET transcription.

Heterogeneous nuclear ribonucleoprotein K and nucleolin as transcriptional activators of the vascular endothelial growth factor promoter through interaction with secondary DNA structures.

The human vascular endothelial growth factor (VEGF) promoter contains a polypurine/polypyrimidine (pPu/pPy) tract that is known to play a critical role in its transcriptional regulation. This pPu/pPy tract undergoes a conformational transition between B-DNA, single-stranded DNA, and atypical secondary DNA structures such as G-quadruplexes and i-motifs. We studied the interaction of the cytosine-rich (C-rich) and guanine-rich (G-rich) strands of this tract with transcription factors heterogeneous nuclear ribonucleoprotein (hnRNP) K and nucleolin, respectively, both in vitro and in vivo and their potential role in the transcriptional control of VEGF. Using chromatin immunoprecipitation (ChIP) assay for our in vivo studies and electrophoretic mobility shift assay (EMSA) for our in vitro studies, we demonstrated that both nucleolin and hnRNP K bind selectively to the G- and C-rich sequences, respectively, in the pPu/pPy tract of the VEGF promoter. The small interfering RNA (siRNA)-mediated silencing of either nucleolin or hnRNP K resulted in the down-regulation of basal VEGF gene, suggesting that they act as activators of VEGF transcription. Taken together, the identification of transcription factors that can recognize and bind to atypical DNA structures within the pPu/pPy tract will provide new insight into mechanisms of transcriptional regulation of the VEGF gene.