A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End Processing Complex.

Alternative polyadenylation (APA) contributes to transcriptome complexity by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3' US) is a common feature of most cancer cells; however, the molecular mechanisms are not understood. Here, we describe a widespread mechanism promoting 3' US in cancer through ubiquitination of the mRNA 3' end processing complex protein, PCF11, by the cancer-specific MAGE-A11-HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11, resulting in loss of CFIm25 from the mRNA 3' end processing complex. This leads to APA of many transcripts affecting core oncogenic and tumor suppressors, including cyclin D2 and PTEN. These findings provide insights into the molecular mechanisms driving APA in cancer and suggest therapeutic strategies.

The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51.

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

Neuroprotective Effects of Geopung-Chunghyuldan Based on Its Salvianolic Acid B Content Using an In Vivo Stroke Model.

BACKGROUND: Geopung-Chunghyuldan (GCD) has neuroprotective properties. Salviae miltiorrhizae Radix plays an essential role in GCD's effect. The Salviae miltiorrhizae Radix marker compound is salvianolic acid B; however, its content is not uniform among samples. This study aimed to evaluate the neuroprotective effects of GCD based on salvianolic acid B content. METHODS: The neuroprotective effects of GCD based on the salvianolic acid B content were evaluated by measuring infarct volume 24 h after permanent middle cerebral artery occlusion in an in vivo stroke model. For the experimental group, each GCD was administered immediately before surgery. The control groups were administered distilled water and aspirin (30 mg/kg) in the same way. The salvianolic acid B content in five types of Salviae Miltiorrhizae Radix (two Chinese and three Korean regions) based on different cultivation regions was analyzed by high-performance liquid chromatography. RESULTS: Three samples met the Korean and Chinese Pharmacopeia standards for salvianolic acid B. However, two samples did not. GCDs with high salvianolic acid B showed marked neuroprotective effects compared to the control groups, whereas GCDs with low salvianolic acid B did not. CONCLUSIONS: The salvianolic acid B content of Salviae miltiorrhizae Radix affects the neuroprotection effect of GCD. Stable, raw Salviae miltiorrhizae Radix is essential for GCD homogenization.

Oncologic Outcomes in Nipple-sparing Mastectomy with Immediate Reconstruction and Total Mastectomy with Immediate Reconstruction in Women with Breast Cancer: A Machine-Learning Analysis.

BACKGROUND: This study used a single-institution cohort, the Severance dataset, validated the results by using the surveillance, epidemiology, and end results (SEER) database, adjusted with propensity-score matching (PSM), and analyzed by using a machine learning method. To determine whether the 5-year, disease-free survival (DFS) and overall survival (OS) of patients undergoing nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) are not inferior to those of women treated with total mastectomy/skin-sparing mastectomy (TM/SSM). METHODS: The Severance dataset enrolled 611 patients with early, invasive breast cancer from 2010 to 2017. The SEER dataset contained data for 485,245 patients undergoing TM and 14,770 patients undergoing NSM between 2000 and 2018. All patients underwent mastectomy and IBR. Intraoperative, frozen-section biopsy for the retro-areolar tissue was performed in the NSM group. The SEER dataset was extracted by using operation types, including TM/SSM and NSM. The primary outcome was DFS for the Severance dataset and OS for the SEER dataset. PSM analysis was applied. Survival outcomes were analyzed by using the Kaplan-Meier method and Cox proportional hazard (Cox PH) regression model. We implemented XGBSE to predict mortality with high accuracy and evaluated model prediction performance using a concordance index. The final model inspected the impact of relevant predictors on the model output using shapley additive explanation (SHAP) values. RESULTS: In the Severance dataset, 151 patients underwent NSM with IBR and 460 patients underwent TM/SSM with IBR. No significant differences were found between the groups. In multivariate analysis, NSM was not associated with reduced oncologic outcomes. The same results were observed in PSM analysis. In the SEER dataset, according to the SHAP values, the individual feature contribution suggested that AJCC stage ranks first. Analyses from the two datasets confirmed no impact on survival outcomes from the two surgical methods. CONCLUSIONS: NSM with IBR is a safe and feasible procedure in terms of oncologic outcomes. Analysis using machine learning methods can be successfully applied to identify significant risk factors for oncologic outcomes.

Vision for tobacco endgame in Korea: suggestions for countries with endgame aspirations.

Tobacco endgame is a focal point of discussion at both national and international levels. We aimed to describe efforts related to achieving the tobacco endgame in the Republic of Korea, an exemplar of a country with endgame aspirations, and compare them with the efforts of other nations. We reviewed the tobacco endgame efforts of three nations considered tobacco control leaders: New Zealand (NZ), Australia and Finland. The efforts/attempts of each country were described using an endgame strategy category. The tobacco control leaders had explicit goals to achieve a smoking prevalence of <5% before a target date and had legislation and research centres for tobacco control and/or endgame. NZ is implementing a mixture of conventional and innovative endgame interventions; the others use incremental conventional approaches. In Korea, there has been an attempt to ban the sale and manufacture of combustible cigarettes. The attempt led to the filing of a petition, and a survey of adults showed 70% supported the legislation banning tobacco. The Korean government mentioned a tobacco endgame in a 2019 plan, yet a target and an end date were absent. The 2019 plan in Korea included incremental FCTC strategies. Practices in the leading countries show that legislation and research are key to ending the tobacco epidemic. The MPOWER measures must be strengthened, endgame objectives must be set and bold strategies must be adopted. Key endgame policies include those with evidence of effectiveness, such as retailer reductions.

Surgical and Oncologic Outcomes of Robotic and Conventional Nipple-Sparing Mastectomy with Immediate Reconstruction: International Multicenter Pooled Data Analysis.

BACKGROUND: Robotic nipple-sparing mastectomy (RNSM) has been developed to reduce conspicuous scar and increase the quality of life in women. This study aimed to evaluate the surgical and oncologic outcomes of RNSM with immediate breast reconstruction (IBR) compared with conventional nipple-sparing mastectomy (CNSM). PATIENTS AND METHODS: This international multicenter, pooled analysis of individual patient-level data enrolled a total of 755 procedures in 659 women (609 had breast cancer and 50 underwent risk-reducing mastectomy) who underwent nipple-sparing mastectomy with IBR. Surgical and oncologic outcomes, including 30-days postoperative (POD 30d) complication rate, nipple necrosis rate, grade of Clavien-Dindo classification, disease-free survival, and overall survival, were evaluated. Propensity score-matched analyses were performed to adjust for confounding factors. RESULTS: The median age of both the RNSM and CNSM groups was 45 years. The RNSM group had lower body mass index (BMI) and a higher proportion of benign disease compared with the CNSM group. POD 30d complications and postoperative complication grade III rates were lower in the RNSM group than in the CNSM group (p < 0.05). The nipple necrosis rate was 2.2% and 7.8% for RNSM and CNSM, respectively (p = 0.002). After propensity score matching, significantly lower rates of POD 30d complications, nipple necrosis, and postoperative complication grade III occurred in the RNSM group than in the CNSM group (all p < 0.05). Oncologic outcomes were not significantly different between the two groups. CONCLUSION: RNSM can provide better cosmetic results with favorable surgical and oncologic outcomes for women with early breast cancer or BRCA mutation.

Second primary malignancy risk in thyroid cancer and matched patients with and without radioiodine therapy analysis from the observational health data sciences and informatics.

PURPOSE: Risk of second primary malignancy (SPM) after radioiodine (RAI) therapy has been continuously debated. The aim of this study is to identify the risk of SPM in thyroid cancer (TC) patients with RAI compared with TC patients without RAI from matched cohort. METHODS: Retrospective propensity-matched cohorts were constructed across 4 hospitals in South Korea via the Observational Health Data Science and Informatics (OHDSI), and electrical health records were converted to data of common data model. TC patients who received RAI therapy constituted the target group, whereas TC patients without RAI therapy constituted the comparative group with 1:1 propensity score matching. Hazard ratio (HR) by Cox proportional hazard model was used to estimate the risk of SPM, and meta-analysis was performed to pool the HRs. RESULTS: Among a total of 24,318 patients, 5,374 patients from each group were analyzed (mean age 48.9 and 49.2, women 79.4% and 79.5% for target and comparative group, respectively). All hazard ratios of SPM in TC patients with RAI therapy were ≤ 1 based on 95% confidence interval(CI) from full or subgroup analyses according to thyroid cancer stage, time-at-risk period, SPM subtype (hematologic or non-hematologic), and initial age (< 30 years or ≥ 30 years). The HR within the target group was not significantly higher (< 1) in patients who received over 3.7 GBq of I-131 compared with patients who received less than 3.7 GBq of I-131 based on 95% CI. CONCLUSION: There was no significant difference of the SPM risk between TC patients treated with I-131 and propensity-matched TC patients without I-131 therapy.

Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis.

In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-η. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here we showed that ISG15 modification (ISGylation) of PCNA plays a key role in TLS termination. Upon UV irradiation, EFP, an ISG15 E3 ligase, bound to mono-ubiquitinated PCNA and promoted its ISGylation. ISGylated PCNA then tethered USP10 for deubiquitination and in turn the release of polymerase-η from PCNA. Eventually, PCNA was deISGylated by UBP43 for reloading of replicative DNA polymerases and resuming normal DNA replication. However, ISGylation-defective Lys-to-Arg mutations in PCNA or knockdown of any of ISG15, EFP, or USP10 led to persistent recruitment of mono-ubiquitinated PCNA and polymerase-η to nuclear foci, causing an increase in mutation frequency. These findings establish a crucial role of PCNA ISGylation in termination of error-prone TLS for preventing excessive mutagenesis.

Evaluation of a Multifaceted Protocol in Reducing Unnecessary Telemetry Monitoring across a Large Healthcare System.

OBJECTIVES: Telemetry is frequently overused in hospitals. The goal of this study was to evaluate a telemetry protocol aimed at decreasing inappropriate telemetry utilization across four different hospitals within a large healthcare system by modifying the electronic telemetry order to incorporate the 2017 American Heart Association practice guidelines on the appropriate use of telemetry and using an electronic nursing screening task form to safely discontinue telemetry. METHODS: We performed a retrospective analysis of telemetry utilization before and after we implemented a protocol across four hospitals within a large healthcare system. We compared the average number of days of telemetry monitoring and hospital length of stay during the preintervention period with the 6-month postintervention period. RESULTS: There were a total of 23,774 encounters evaluated. There was a statistically and clinically significant 24% decrease in telemetry duration between pre- and postintervention time periods (P < 0.0001). The mean (standard error) telemetry duration was 4.11 (0.17) and 2.36 (0.13) days in pre- and postintervention periods, respectively. CONCLUSIONS: The results of our study demonstrate a statistically significant decrease in overall duration of telemetry monitoring by nearly 1.75 days across each of the four hospitals with the implementation of a multifaceted telemetry protocol that included hardwiring the American Heart Association practice guidelines into the electronic order and using a nursing-driven discontinuation protocol.

Treatment evaluation of Kami Guibi-tang on participants with amnestic mild cognitive impairment using magnetic resonance imaging on brain metabolites, gamma-aminobutyric acid, and cerebral blood flow.

PURPOSE: To evaluate the effectiveness of Kami Guibi-tang (KGT) in the treatment of mild cognitive impairment (MCI) using magnetic resonance imaging (MRI) on brain metabolites, neurotransmitter, and cerebral blood flow (CBF). METHODS: We randomly allocated a total of 30 MCI patients to a KGT (N = 16) or a placebo (N = 14) group and performed MRI scans before and after 24 weeks of treatment. The participants underwent brain magnetic resonance spectroscopy and MRI scans to obtain brain metabolites using Point-RESolved Spectroscopy (PRESS) single-voxel spectroscopy, gamma-aminobutyric acid (GABA) neurotransmitter using Mescher-Garwood PRESS, and CBF using pseudocontinuous arterial spin labeling sequences using a 3.0 Tesla MRI system. We analyzed metabolite and neurotransmitter levels and CBF using repeated-measure analysis of variance to evaluate between-subject group effect, within-subject treatment condition effect, and interaction of group by condition (group x condition). RESULTS: The GABA+/creatine (Cr) ratio values were not significantly different between the before and after treatment conditions. The glutamate complex/Cr ratio difference before and after treatment was lower in the KGT group than in the placebo group, but was not statistically significant (p = 0.077). The result of region of interest-based CBF measurement showed that CBF values were significantly lower after treatment at Cluster 2 for the KGT group (p = 0.003) and the placebo group (p = 0.011), at hippocampus for the KGT group (p = 0.004) and the placebo group (p = 0.008), and at the fusiform gyrus for the KGT group (p = 0.002). Furthermore, the absolute CBF difference before and after treatment in the fusiform gyrus was significantly lower in the KGT group than in the placebo group (p = 0.024). CONCLUSIONS: Although a KGT treatment of 24 weeks showed some significant impact on the level of CBF, the Korean version of the mini-mental state examination score was not significantly different between before and after treatment conditions, indicating that there was no memory function improvement after treatment in amnestic MCI patients. Therefore, further studies should be performed with a relatively larger population and extending the duration of the KGT treatment.

Atrial Fibrillation is Strongly Associated With the Neutrophil to Lymphocyte Ratio in Acute Ischemic Stroke Patients: A Retrospective Study.

BACKGROUND: No study has investigated the relationship between hospital-admission neutrophil and lymphocyte ratio (NLR) and various stroke risk factors. We sought to determine which stroke risk factor could be the most appropriate predictor of NLR in acute ischemic stroke. METHODS: We collected data on various stroke risk factors and National Institutes of Health Stroke Scale (NIHSS) score in 1,053 acute ischemic stroke patients. The regression analysis was adjusted for confounding factors such as stroke risk factors. RESULTS: There was a trend of increased NLR with a rise in alcohol consumption, the prevalence of hypertension, cardioembolism (CE) etiology, the NIHSS scores in men and the prevalence of atrial fibrillation, other heart diseases, CE and small vessel occlusion etiology and the NIHSS scores in women. Multiple linear regression analyses, adjusted for confounding factors, showed that the atrial fibrillation and NIHSS scores in men and atrial fibrillation, diabetes mellitus as well as NIHSS scores in women had a significant positive association with NLR. However, a negative association was showed for body mass index (BMI). CONCLUSION: We confirmed that the atrial fibrillation can be a predictor of high NLR in acute stroke patients, and diabetes mellitus as well as low BMI could be a predictor of high NLR in female acute ischemic stroke patients.

USP47 and C terminus of Hsp70-interacting protein (CHIP) antagonistically regulate katanin-p60-mediated axonal growth.

Katanin is a heterodimeric enzyme that severs and disassembles microtubules. While the p60 subunit has the enzyme activity, the p80 subunit regulates the p60 activity. The microtubule-severing activity of katanin plays an essential role in axonal growth. However, the mechanisms by which neuronal cells regulate the expression of katanin-p60 remains unknown. Here we showed that USP47 and C terminus of Hsp70-interacting protein (CHIP) antagonistically regulate the stability of katanin-p60 and thereby axonal growth. USP47 was identified as a katanin-p60-specific deubiquitinating enzyme for its stabilization. We also identified CHIP as a ubiquitin E3 ligase that promotes proteasome-mediated degradation of katanin-p60. Moreover, USP47 promoted axonal growth of cultured rat hippocampal neurons, whereas CHIP inhibited it. Significantly, treatment with basic fibroblast growth factor (bFGF), an inducer of axonal growth, increased the levels of USP47 and katanin-p60, but not CHIP. Consistently, bFGF treatment resulted in a marked decrease in the level of ubiquitinated katanin-p60 and thereby in the promotion of axonal growth. On the other hand, the level of USP47, but not CHIP, decreased concurrently with that of katanin-p60 as axons reached their target cells. These results indicate that USP47 plays a crucial role in the control of axonal growth during neuronal development by antagonizing CHIP-mediated katanin-p60 degradation.

Moderate-Intensity Rosuvastatin/Ezetimibe Combination versus Quadruple-Dose Rosuvastatin Monotherapy: A Meta-Analysis and Systemic Review.

PURPOSE: There are few studies in the literature on the dosage of statin that equivalently reduces low-density lipoprotein cholesterol (LDL-C) compared to an ezetimibe combination and whether such regimens have differences in safety. We compared the lipid-modifying efficacy and safety of 5 mg rosuvastatin/10 mg ezetimibe to those of 20 mg rosuvastatin. MATERIALS AND METHODS: A literature search was conducted using the PubMed, EMBASE, Cochrane, Web of Sciences, and SCOPUS databases up to December 2021. Human studies investigating the two aforementioned regimens with a randomized controlled design were selected. Outcome variables included the percentage reduction in LDL-C and other lipid parameters and rates of composite adverse events (AEs), including muscle-related symptoms. A random-effects meta-analysis was performed after heterogeneity testing between studies. RESULTS: Seven studies were included in this meta-analysis. The percentage LDL-C reduction did not differ between the combination and monotherapy groups [standardized mean difference (SMD) 0.08; 95% confidence interval (CI) -0.09 to 0.26; p=0.35]. The risk of composite AEs (odds ratio 0.50; 95% CI 0.15 to 1.72; p=0.27) of the combination was not different compared to the monotherapy group. The percentage of total cholesterol reduction was greater in the combination group (SMD 0.22; p=0.02), whereas that of triglyceride reduction and high-density lipoprotein cholesterol elevation did not differ between the two groups. CONCLUSION: This meta-analysis showed that 5 mg rosuvastatin/10 mg ezetimibe had largely comparable lipid-modifying efficacy and tolerability as 20 mg rosuvastatin.

The usefulness of quantitative 99mTc-HMPAO WBC SPECT/CT for predicting lower extremity amputation in diabetic foot infection.

We investigated the usefulness of quantitative 99mTc-white blood cell (WBC) single photon emission computed tomography (SPECT)/computed tomography (CT) for predicting lower extremity amputation in diabetic foot infection (DFI). A total of 93 feet of 83 consecutive patients with DFI who underwent WBC SPECT/CT for treatment planning were retrospectively analysed. The clinical and SPECT/CT parameters were collected along with the measurements of the maximum standardized uptake value (SUVmax) at DFI. Statistical logistic regression analysis was performed to explore the predictors of LEA and receiver operating characteristic (ROC) curve was analysed to assess the predictive value of SPECT/CT. The independent predictors of amputation were previous amputation (OR 11.9), numbers of SPECT/CT lesions (OR 2.1), and SUVmax of DFI; either continuous SUVmax (1-increase) (OR 1.3) or categorical SUVmax > 1.1 (OR 21.6). However, the conventional SPECT/CT interpretation failed to predict amputation. In ROC analysis, the SUVmax yielded a fair predictor (area under the curve (AUC) 0.782) of amputation. The model developed from these independent predictors yielded an excellent performance for predicting amputation (AUC 0.873). Quantitative WBC SPECT/CT can provide new information useful for predicting the outcomes and guiding treatment for patients with DFI.

Prognostic Value of Radiomic Analysis Using Pre- and Post-Treatment 18F-FDG-PET/CT in Patients with Laryngeal Cancer and Hypopharyngeal Cancer.

BACKGROUND: The prognostic value of conducting 18F-FDG PET/CT imaging has yielded different results in patients with laryngeal cancer and hypopharyngeal cancer, but these results are controversial, and there is a lack of dedicated studies on each type of cancer. This study aimed to evaluate whether combining radiomic analysis of pre- and post-treatment 18F-FDG PET/CT imaging features and clinical parameters has additional prognostic value in patients with laryngeal cancer and hypopharyngeal cancer. METHODS: From 2008 to 2016, data on patients diagnosed with cancer of the larynx and hypopharynx were retrospectively collected. The patients underwent pre- and post-treatment 18F-FDG PET/CT imaging. The values of ΔPre-Post PET were measured from the texture features. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select the most predictive features to formulate a Rad-score for both progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curve analysis and Cox regression were employed to assess PFS and OS. Then, the concordance index (C-index) and calibration plot were used to evaluate the performance of the radiomics nomogram. RESULTS: Study data were collected for a total of 91 patients. The mean follow-up period was 71.5 mo. (8.4-147.3). The Rad-score was formulated based on the texture parameters and was significantly associated with both PFS (p = 0.024) and OS (p = 0.009). When predicting PFS, only the Rad-score demonstrated a significant association (HR 2.1509, 95% CI [1.100-4.207], p = 0.025). On the other hand, age (HR 1.116, 95% CI [1.041-1.197], p = 0.002) and Rad-score (HR 33.885, 95% CI [2.891-397.175], p = 0.005) exhibited associations with OS. The Rad-score value showed good discrimination when it was combined with clinical parameters in both PFS (C-index 0.802-0.889) and OS (C-index 0.860-0.958). The calibration plots also showed a good agreement between the observed and predicted survival probabilities. CONCLUSIONS: Combining clinical parameters with radiomics analysis of pre- and post-treatment 18F-FDG PET/CT parameters in patients with laryngeal cancer and hypopharyngeal cancer might have additional prognostic value.

The effectiveness of Kami Guibi-tang for cognitive impairment patients: A retrospective chart review.

Background: and Purpose: The number of patients with cognitive impairment is increasing worldwide. Therapeutic drugs that slow disease progression are being developed; however, further research is required. This study investigated the effects of Kami Guibi-tang on patients with various types of cognitive decline. Methods: This study was a single-center, retrospective chart review of patients who visited KyungHee University Hospital at Gangdong from January 2015 to March 2022. The study included participants who took Kami Guibi-tang for more than 90 days and were assessed on the Korean version Mini-Mental State Examination (MMSE-K) scores before and after treatment. Participants who received other liquid herbal medicines during the treatment were excluded. The outcome of interest was changed scores in MMSE-K and Short form of Geriatric Depression Scale (S-GDS). Results: A total of 31 participants were included. The total MMSE-K score significantly increased with time and showed a significant increase at 3 and 9 months compared with baseline. Among the MMSE-K subscores, the orientation subscore showed a significant increase at three months compared with baseline, and the attention and calculation subscore showed a significant increase with time. In addition, four participants with vascular dementia showed a significant increase in the total MMSE-K score over time and a significant increase after 9 months compared with baseline. The S-GDS score in 31 participants showed a significant decrease with time and at all time points compared with baseline. Conclusions: Kami Guibi-tang may improve cognitive function in patients with cognitive decline.

Prevention of inflammation-mediated neurotoxicity by butylidenephthalide and its role in microglial activation.

Microglial cells are the prime effectors in immune and inflammatory responses of the central nervous system (CNS). During pathological conditions, the activation of these cells helps restore CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory molecules and neurotoxins. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target neurodegeneration, such as that in Alzheimer's and Parkinson's diseases. The rhizome of Ligusticum chuanxiong Hort. (Ligusticum wallichii Franch) has been widely used for the treatment of vascular diseases in traditional oriental medicine. Butylidenephthalide (BP), a major bioactive component from L. chuanxiong, has been reported to have a variety of pharmacological activities, including vasorelaxant, anti-anginal, anti-platelet and anti-cancer effects. The aim of this study was to examine whether BP represses microglial activation. In rat brain microglia, BP significantly inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), tumour necrosis factor-α and interleukin-1ß. In organotypic hippocampal slice cultures, BP clearly blocked the effect of LPS on hippocampal cell death and inhibited LPS-induced NO production in culture medium. These results newly suggest that BP provide neuroprotection by reducing the release of various proinflammatory molecules from activated microglia.

Role of combined BI-RADS assessment using mammography and sonography for evaluation of incidental hypermetabolic lesions in the breast on 18F-FDG PET-CT.

BACKGROUND: PET-CT is widely used for evaluation and follow-up of malignancy. Incidental hypermetabolic lesions are often found on PET-CT, some of which are confirmed to be malignant. PURPOSE: To estimate the role of combined Breast Imaging-Reporting and Data System (BI-RADS) assessment using mammography and sonography for evaluation of incidental hypermetabolic lesions on 18F-FDG PET-CT and to determine an appropriate next step. MATERIAL AND METHODS: This study included incidental hypermetabolic lesions found in the breasts of 7594 women who underwent PET-CT at three university-affiliated hospitals between January 2006 and December 2011. We reviewed the maximum standardized uptake value (SUVmax) of incidental lesions, combined BI-RADS assessment of mammography and sonography, and final results. We analyzed the negative predictive values of the probably benign (categories 1-3) group and the sensitivity of suspicious (categories 4 and 5) groups according to combined BI-RADS assessment. RESULTS: Forty-three patients (0.6%) had 49 incidental hypermetabolic lesions in the breast. Histologic diagnosis in 17 patients confirmed nine breast cancers (27.3%). Sixteen patients underwent imaging follow-up for at least 2 years; no breast cancer was detected. Thirteen patients were lost to follow-up and were excluded. For the suspicious (n = 14) and probably benign (n = 19) groups according to combined BI-RADS assessment, both the sensitivity and negative predictive values were 100%. Using an optimal diagnostic cut-off value of 2.15, the malignancy rate was not significantly different (16.7% vs. 45.5%, respectively, in the group with SUVmax < 2.15 and the group with SUVmax ≥ 2.15; P > 0.05). The SUVmax of the confirmed malignant and assumed benign groups were not significantly different (3.1% vs. 2.2%, respectively; P > 0.05). CONCLUSION: Both mammography and sonography should be considered the next step to evaluate incidental hypermetabolic lesions on 18F-FDG PET-CT because combined BI-RADS assessment provides an excellent negative predictive value for excluding malignancy.

Huge tophaceous pseudogout associated with tenosynovial chondromatosis arising from flexor digitorum tendon sheaths of the foot: a case report.

Synovial chondromatosis (SC) is a benign proliferative process of synovial tissue creating multiple cartilaginous nodules in joints. It most commonly occurs in the large joints of the knee, hip, and shoulder, uncommonly in the small joints of the hand and foot, and only rarely in the tenosynovial membrane of tendon sheath, termed tenosynovial chondromatosis (TC). Unlike SC, TC predisposes to the foot or hand. The rarity and unfamiliarity of imagers with TC, as well as the variability of its histologic features often lead to an erroneous diagnosis of extraskeletal chondroma or even chondrosarcoma as in the present case. Calcium pyrophosphate dehydrate (CPPD) crystals are usually deposited in the articular cartilage or periarticular structures such as synovium and capsule, and rarely in other soft tissue structures including bursa, tendon, subcutaneous tissue, and dura mater. CPPD crystals may also be deposited in extraskeletal chondroma and SC. We present an exceptionally rare case of huge tophaceous pseudogout associated with TC that is considered to arise from the flexor digitorum longus tendon sheaths of the foot, initially mistaken for a chondrosarcoma.