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Patients with triple-negative breast cancer (TNBC) often develop metastases in visceral organs including the liver, but the detailed molecular mechanisms of TNBC liver metastasis is not clearly understood. In this study, we tried to dissect the process of pre-metastatic niche formation in the liver by using patient-derived xenograft (PDX) models of TNBC with different metastatic propensity. RNA sequencing of TNBC PDX models that successfully metastasized to liver showed upregulation of the Cx3cr1 gene in the liver microenvironment. In syngeneic breast cancer models, the Cx3cr1 upregulation in liver preceded the development of cancer cell metastasis and was the result of recruitment of CX3CR1-expressing macrophages. The recruitment was induced by the CX3CL1 production from the liver endothelial cells and this CX3CL1–CX3CR1 signaling in the pre-metastatic niche resulted in upregulation of MMP9 that promoted macrophage migration and cancer cell invasion. In addition, our data suggest that the extracellular vesicles derived from the breast cancer cells induced the TNFα expression in liver, which leads to the CX3CL1 upregulation. Lastly, the plasma CX3CL1 levels in 155 patients with breast cancer were significantly associated with development of liver metastasis. Implications: Our data provides previously unknown cascades regarding the molecular education of pre-metastatic niche in liver for TNBC.

Purpose: Robot-assisted nipple-sparing mastectomy (RANSM) improves cosmetic outcomes compared to conventional nipple-sparing mastectomy (CNSM) since RANSM is performed with minimal incisions. However, there are few studies on the feasibility and surgical outcome of RANSM. The aim of this study was to compare the surgical outcomes of RANSM and CNSM in breast cancer patients. Method: A retrospective observational study was conducted at our institution between January 2021 and December 2021. A total of 54 patients diagnosed with breast malignancy that underwent either a robotic-assisted or conventional nipple-sparing mastectomy were included. The demographics of the patient’s sex, age, body mass index (BMI), breast weight, and preoperative diagnosis were investigated. The surgical method, operation time (including docking time and console time in the case of robotic surgery), postoperative complications, length of hospital stay, pain score, and adjuvant therapy were analyzed. Result: A total of 57 breasts in 54 female patients were included in the study: 36 invasive ductal carcinoma patients, 11 ductal carcinoma cases, 6 invasive lobular carcinoma, 2 mucinous carcinoma, one solid papillary carcinoma and one lobular carcinoma in situ. A median age of 49(27-66), mean BMI of 22 (18.89-26.28), and mean breast weight was 246 g (120-305g). The mean operation time was 122 minutes (robotic 140 vs. conventional 118), and the average docking time was five minutes and console time 60 minutes in the robot-assisted surgery. There was only one postoperative complication in the robot group and ten cases in the conventional group. The mean hospital stay was 12.6 days (RANSM 10.75 vs. CNSM 12.92), and the average pain score was 3.53 (RANSM 3.50 vs. CNSM 3.54). None needed adjuvant therapy in the robot group. In the conventional surgical group, four patients underwent adjuvant radiotherapy and sixteen patients underwent chemotherapy including six neoadjuvant cases. Conclusion: Our results showed that RANSM had advantages of shorter hospitalization and lower pain scores although it had slightly longer operation time and could not applicable in relatively large breasts. In the near future, RANSM may be considered as the surgery of choice over CNSM in breast cancer patients. Citation Format: Ji Young You, Haemin Lee, Eun-Shin Lee, Seung Pil Jung. Comparison of robot-assisted nipple sparing mastectomy with conventional nipple sparing mastectomy: a single-center experience. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-20.

Background Malignant phyllodes tumour (MPT) is a rare breast malignancy with epithelial and mesenchymal features. Currently, there are no appropriate research models or effective targeted therapeutic approaches for MPT. Methods We collected fresh frozen tissues from nine patients with MPT and performed whole-exome and RNA sequencing. Additionally, we established patient-derived xenograft (PDX) models from patients with MPT and tested the efficacy of targeting dysregulated pathways in MPT using the PDX model from one MPT. Results MPT has unique molecular characteristics when compared to breast cancers of epithelial origin and can be classified into two groups. The PDX model derived from one patient with MPT showed that the mouse epithelial component increased during tumour growth. Moreover, targeted inhibition of platelet-derived growth factor receptor (PDGFR) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) by imatinib mesylate and PKI-587 showed in vivo tumour suppression effects. Conclusions This study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT.

Supplementary Table 1. Information about patients derived xenograft models and derived patient. Supplementary Table 2. Ontology of differentially expressed genes in metastasis-harboring liver of PDX models. Supplementary Table 3. Differentially expressed genes in liver and lung of metastasis-harboring PDX models. Supplementary Table 4. Human ratio in lung and liver of additional PDX models identified by RNA sequencing. Supplementary Table 5. Gene ontology of co-expressed genes with Cx3cr1 in liver of PDX models identified by RNA sequencing. Supplementary Table 6. Top ranked genes having significant correlation with Cx3cr1 in liver of PDX models identified by RNA sequencing. Supplementary Table 7. Demographic and clinical characteristics of all patients. Supplementary Table 8. Information about used primer sequences for quantitative real-time PCR Supplementary Figure 1. Liver and lung H&E staining pictures of eight nonmetastatic PDX models a. Microscopic images of non-metastasis harboring PDX mouse model's liver (left) and lung (right) taken at 400x magnification. Supplementary Figure 2. Immunohistochemistry about CX3CR1 in liver and lung of breast cancer metastasis patients. Supplementary Figure 3. Hepatic metastasis after four weeks after orthotopic injection of 4T1 breast cancer cells identified by H&E staining. Supplementary Figure 4. Identification of pre-metastatic niche in liver tissues of 4T1 bearing mice a. mRNA expression of inflammation associated genes identified by real-time PCR in liver tissues of 4T1 bearing mice. Supplementary Figure 5. Identification of CX3CR1 positive cell population. Supplementary Figure 6. FACS analysis with anti-CX3CR1 of Raw264.7 macrophage cell lines. Supplementary Figure 7. Trans-well migration assay of BMDM with or without CX3CL1. Supplementary Figure 8. Mmp9 mRNA expression having significant correlation with Cx3cr1 mRNA expression in liver of PDX models. Supplementary Figure 9. MMP9 expression of macrophages with CX3CL1 treatment. Supplementary Figure 10. Signaling pathway of CX3CL1 treated macrophages. Supplementary Figure 11. Splenic injection of 4T1 cells inducing hepatic metastasis within two weeks in most cases. Supplementary Figure 12. mRNA expression about Cx3cr1 and Mmp9 in liver of vehicle or AZD8797 treated BALB/C mice identified by real-time PCR. Supplementary Figure 13. Correlation plot of Tnfa and Cx3cr1 mRNA expression in liver and lung of PDX models. Supplementary Figure 14. EVs isolation of CD63-mRuby-4T1.

In this study, we investigated the effects of carbonated water concentration on swallowing function using surface electromyography (sEMG). Healthy subjects (n = 52, 26.77 ± 3.21 years old) were asked to perform two swallows each of noncarbonated water, low-concentration carbonated water, medium-concentration carbonated water, and high-concentration carbonated water. Onset time, the mean sEMG activity amplitude, and duration of muscle activity in each swallow were measured and analyzed for orbicularis oris, masseter, submental muscle complex and infrahyoid muscles. Onset time significantly decreased and mean sEMG activity amplitude significantly increased with carbonation concentration. Therefore, stimulation with carbonation can be effective for modulating a faster and stronger swallow in the oral and pharyngeal phases of swallowing, and its effect on amplitude was greater in the oral phase than in the pharyngeal phase.Clinical Trials Registration This study is registered with Clinical Research Information Service (KCT0005925).

Background Mammography screening has been proven to detect breast cancer at an early stage and reduce mortality; however, it has low accuracy in young women or women with dense breasts. Blood-based diagnostic tools may overcome the limitations of mammography. This study assessed the diagnostic performance of a three-protein signature in patients with suspicious breast lesions. Findings This trial (MAST; KCT0004847) was a prospective multicenter observational trial. Three-protein signature values were obtained using serum and plasma from women with suspicious lesions for breast malignancy before tumor biopsy. Additionally, blood samples from women who underwent clear or benign mammography were collected for the assays. Among 642 participants, the sensitivity, specificity, and overall accuracy values of the three-protein signature were 74.4%, 66.9%, and 70.6%, respectively, and the concordance index was 0.698 (95% CI 0.656, 0.739). The diagnostic performance was not affected by the demographic features, clinicopathologic characteristics, and co-morbidities of the participants. Conclusions The present trial showed an accuracy of 70.6% for the three-protein signature. Considering the value of blood-based biomarkers for the early detection of breast malignancies, further evaluation of this proteomic assay is warranted in larger, population-level trials. This Multi-protein Assessment using Serum to deTermine breast lesion malignancy (MAST) was registered at the Clinical Research Information Service of Korea with the identification number of KCT0004847 (https://cris.nih.go.kr).

Although adjuvant chemotherapy (CTx) is still recommended for high-risk patients with hormone receptor-positive and human epidermal receptor (HER)-2-negative breast cancer, recent studies found that selected patients with low disease burden may be spared from CTx and receive hormonal treatment (HT) alone. This study aims to evaluate the trends of treatment (CTx + HTThe Korean Breast Cancer Society Registry was queried (2000 to 2018) for women with pT1-2N0-1 hormone receptor-positive and HER2-negative disease who underwent surgery and adjuvant systemic treatment (CTx and HT). Clinicopathologic factors, change in pattern of treatment over time, and OS for each treatment option were analyzed.A total of 40,938 women were included in the study; 20,880 (51.0%) received CTx + HT, while 20,058 (49.0%) received HT only. In recent years, there has been a steady increase in the use of HT alone, from 21.0% (2000) to 64.6% (2018). In Cox regression analysis, age, type of breast and axillary operations, T and N stages, body mass index, histologic grade, and presence of lymphovascular invasion were prognostic indicators for OS. There was no significant difference between CTx + HT and HT alone in terms of OS (P = 0.126).Over the years, there has been a shift from CTx + HT to HT alone without a significant difference in OS. Therefore, HT alone could be a safe treatment option in selected patients, even those with T2N1 disease.

Objective To retrospectively review the characteristics of preschool children with speech and language disorders to determine their clinical features and compares the average degrees of language delay based on hospital visit purposes, language developmental delay causes, and maternal language.Methods One thousand one hundred two children (832 males, 270 females) with the chief complaint of language or speech problems who underwent language assessment for the first time were included. Their medical records, including demographic data, language environments, and family history of language problems and other developmental problems, were collected. Furthermore, the results of language and developmental assessments and hearing tests were collected.Results Among the children enrolled in this study, 24% had parental problems and 9% were nurtured by their grandparents. The average degree of language delay did not differ regarding purposes of hospital visits. The average degree of language delay was greatest in children with autism spectrum disorders and least in children with mixed receptive–expressive language disorders. In children with mothers who do not speak Korean as their native language, social quotients in the social maturity scale were less than 70.Conclusion Language environment is an essential factor that may cause speech and language disorders. Moreover, maternal language seems to affect the social quotient of the social maturity scale.

Introduction Sarcopenia is known as a risk factor for falls and hip fracture, and understanding fall characteristics is important for the fall-prevention programs. The aim of this study is to investigate whether sarcopenia is associated with fall characteristics in older adults with fragility hip fracture. Methods A cross-sectional study was conducted in 147 patients over 65 years of age who had undergone a two-week postoperative rehabilitation for hip fracture. Fall characteristics included the fall type, direction and location. Fall types were categorized into two groups: fragile falls, leg weakness during walking, changing positions or standing; non-fragile falls, slipping or tripping while walking. Correlations between sarcopenia and fall characteristics, and of fall type with sarcopenia and fall characteristics were analyzed. Logistic regression analyzes were used to identify independent risk factors for fragile falls. Results Sarcopenia was significantly correlated with fragile falls (r = .222, p = .007) and was more prevalent in the fragile fall group than the non-fragile fall group (53.5% vs. 32.9%). Sarcopenia (OR = 2.354, 95% CI 1.177–4.709, p = .016), moderate comorbidities (OR = 3.572, 95% CI 1.109–11.501, p = .033) and severe comorbidities (OR = 5.396, 95% CI 1.476–19.729, p = .011) by the Charlson Comorbidity Index were significant independent risk factors for fragile falls. Conclusions Sarcopenia was correlated with fragile falls; moreover, it was a risk factor for all of these fall types in older adults with fragility hip fracture. Based on these associations, targeted fall-prevention programs for older adults with sarcopenia, a high risk factor of falls and fractures, could help reduce the incidence rates of falls and fragility hip fracture.

Background Aromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen. Methods We analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE. Results We included 47,569 women for the final analysis. Patients were classified into ‘No hormonal treatment (n = 18,807), ‘Switch (n = 2097)’, ‘Tamoxifen (n = 7081)’ and ‘AI (n = 19,584)’. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74–0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84–1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47–0.84). Conclusions Our results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE., Highlights • Controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen. • The protective effect of tamoxifen against cardiovascular events in elderly breast cancer patients that is not seen with AIs. • Choice of hormonal therapy depends on patient’s cardiovascular or cerebrovascular risks.

PurposeHereditary cancer syndrome means that inherited genetic mutations can increase a person's risk of developing cancer. We assessed the frequency of germline mutations using an nextgeneration sequencing (NGS)–based multiple-gene panel containing 64 cancer-predisposing genes in Korean breast cancer patients with clinical features of hereditary breast and ovarian cancer syndrome (HBOC).Materials and MethodsA total of 64 genes associated with hereditary cancer syndrome were selected for development of an NGS-based multi-gene panel. Targeted sequencing using the multi-gene panel was performed to identify germline mutations in 496 breast cancer patients with clinical features of HBOC who underwent breast cancer surgery between January 2002 and December 2017.ResultsOf 496 patients, 95 patients (19.2%) were found to have 48 deleterious germline mutations in 16 cancer susceptibility genes. The deleterious mutations were found in 39 of 250 patients (15.6%) who had breast cancer and another primary cancer, 38 of 169 patients (22.5%) who had a family history of breast cancer (≥ 2 relatives), 16 of 57 patients (28.1%) who had bilateral breast cancer, and 29 of 84 patients (34.5%) who were diagnosed with breast cancer at younger than 40 years of age. Of the 95 patients with deleterious mutations, 60 patients (63.2%) had BRCA1/2 mutations and 38 patients (40.0%) had non-BRCA1/2 mutations. We detected two novel deleterious mutations in BRCA2 and MLH1.ConclusionNGS-based multiple-gene panel testing improved the detection rates of deleterious mutations and provided a cost-effective cancer risk assessment.

Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC). After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5 cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed. pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormone receptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5 cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%). Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.

As sequencing technology and information of the genomic causes for cancer development expand, multi-gene panel testing for hereditary cancer is increasing in clinical practice. In this chapter, we reviewed the application of multi-gene panel with pre-/post- testing considerations and summarized genetic counseling based on panel testing results in clinical field. In addition, we introduce multi-gene panel for hereditary cancer developed in Seoul National University Hospital.

As sequencing technology and information of the genomic causes for cancer development expand, multi-gene panel testing for hereditary cancer is increasing in clinical practice. In this chapter, we reviewed the application of multi-gene panel with pre-/post- testing considerations and summarized genetic counseling based on panel testing results in clinical field. In addition, we introduce multi-gene panel for hereditary cancer developed in Seoul National University Hospital.

Background Previous randomized trials, performed decades ago, showed no survival benefit of intensive screening for distant metastasis in breast cancer. However, recent improvements in targeted therapies and diagnostic accuracy of imaging have again raised the question of the clinical benefit of screening for distant metastasis. Therefore, we investigated the association between the use of modern imaging and survival of patients with breast cancer who eventually developed distant metastasis.Methods We retrospectively reviewed data of 398 patients who developed distant metastasis after their initial curative treatment between January 2000 and December 2015.Results Patients in the less-intensive surveillance group (LSG) had significantly longer relapse-free survival than did patients in the intensive surveillance group (ISG) (8.7 vs. 22.8 months; p = 0.002). While the ISG showed worse overall survival than the LSG did (50.2 vs. 59.9 months; p = 0.015), the difference was insignificant after adjusting for other prognostic factors. Among the 200 asymptomatic patients whose metastases were detected on imaging, the intensity of screening did not affect overall survival. A small subgroup of patients showed poor survival outcomes when they underwent intensive screening. Patients with HR-/HER2+ tumors and patients who developed lung metastasis in the LSG had worse overall survival than those in the ISG did.Conclusions Highly intensive screening for distant metastasis in disease-free patients with breast cancer was not associated with significant survival benefits, despite the recent improvements in therapeutic options and diagnostic techniques.

Background. The complications after stroke inhibit functional recovery and worsen the prognosis of patients. The implementation of a critical pathway (CP) can facilitate functional recovery after stroke by enabling comprehensive and systematic structured rehabilitation. Objective. To evaluate the effects of the implementation of CP in stroke patients for 10 years. Methods. The data were collected from 960 patients who were diagnosed with a stroke at the university hospital emergency room, who were transferred to the rehabilitation center after the acute phase, and who were discharged after undergoing comprehensive rehabilitation. Based on data collected over a period of 10 years, changes in demographic and stroke characteristics, preexisting medical conditions, poststroke complications, and functional states, as well as length of stay (LOS), were evaluated before and after CP implementation. The modified Rankin Scale (mRS) and the Korean version of the Modified Barthel Index (K-MBI) were used to evaluate functional states. Results. There were no significant differences in demographic and stroke characteristics before and after CP implementation. For those with preexisting medical conditions, there was no significant difference between before and after CP implementation. The majority of the complications were significantly decreased after the implementation of CP. Except for hemorrhagic stroke patients, the Brunnstrom stage in the ischemic and total stroke patients after CP implementation was significantly increased in the upper and lower extremities. The total hospitalization LOS and rehabilitation center hospitalization times were significantly reduced in ischemic and total stroke patients. There was no statistically significant difference in the functional gain of K-MBI and the efficiency of rehabilitation between before and after CP implementation. Conclusion. The implementation of CP allows for better application of evidence- and guideline-based key interventions and helps to provide early, comprehensive, organized, and more specialized care to stroke patients. Despite limited evidence, CP is still recommended as a means of promoting best practices in hospital care for stroke patients.

To retrospectively review the characteristics of preschool children with speech and language disorders to determine their clinical features and compares the average degrees of language delay based on hospital visit purposes, language developmental delay causes, and maternal language.One thousand one hundred two children (832 males, 270 females) with the chief complaint of language or speech problems who underwent language assessment for the first time were included. Their medical records, including demographic data, language environments, and family history of language problems and other developmental problems, were collected. Furthermore, the results of language and developmental assessments and hearing tests were collected.Among the children enrolled in this study, 24% had parental problems and 9% were nurtured by their grandparents. The average degree of language delay did not differ regarding purposes of hospital visits. The average degree of language delay was greatest in children with autism spectrum disorders and least in children with mixed receptive-expressive language disorders. In children with mothers who do not speak Korean as their native language, social quotients in the social maturity scale were less than 70.Language environment is an essential factor that may cause speech and language disorders. Moreover, maternal language seems to affect the social quotient of the social maturity scale.

OBJECTIVE To determine the prevalence and related characteristics of carpal tunnel syndrome (CTS) in orchardists and to investigate the association between electrodiagnostic severity and physical examinations. METHODS Between July 2013 and September 2014, 377 subjects (174 men and 203 women) visited the Gyeongsang National University Hospital's Center for Farmer's Safety and Health. All the subjects underwent electrodiagnostic tests and physical examination, including Phalen's test, Tinel's sign, and Durkan's carpal compression test (CCT). The subjects were classified into 2 groups, the normal group and the CTS group, according to electrodiagnostic test results. To determine the related characteristics of CTS, potential variables, including age, sex, drinking, smoking, body mass index, waist circumference, and total work time, were compared between the 2 groups. The association between electrodiagnostic severity and physical examinations was analyzed. RESULTS CTS was diagnosed in 194 subjects based only on electrodiagnostic test results, corresponding to a prevalence of 51.5%. Among the variables, mean age (p=0.001) and total work time (p=0.007) were significantly correlated with CTS. With respect to the physical examinations, low specificities were observed for Tinel's sign, Phalen's test, and Durkan's CCT (38.4%, 36.1%, and 40.9%, respectively) in the subjects aged ≥65 years. In addition, Phalen's test (p=0.003) and Tinel's sign (p=0.032) in men and Durkan's CCT (p=0.047) in women showed statistically significant differences with increasing CTS severity. The odds ratio was 2.066 for Durkan's CCT in women according to the multivariate logistic regression analysis. CONCLUSION CTS prevalence among orchardists was high, and Durkan's CCT result was significantly quantitatively correlated with the electrodiagnostic test results. Therefore, Durkan's CCT is another reliable examination method for CTS.

TWIK (tandem-pore domain weak inward rectifying K+)-related spinal cord K+ channel (TRESK), a member of the two-pore domain K+ channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TGTRESK). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI (p &lt, 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TGTRESK SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TGTRESK mice showed lower TNF-&alpha, concentrations in the blood than WT mice. In addition, IL-1&beta, concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TGTRESK SCI mice compared to WT-SCI mice (p &lt, 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes.

While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

Purpose Studies have suggested a potential role of patient’s co-morbidity in determining the survival outcomes of breast cancer. In this study, we examined the long-term oncologic outcomes in breast cancer patients who underwent curative surgery according to their pre-existing comorbid conditions and analyzed the association between the co-morbidity and the use of adjuvant therapies. Methods The medical records of 2,501 patients who underwent surgery for primary breast cancer from June 2006 to June 2010 were reviewed retrospectively. The patients were classified into three groups according to preoperative ASA status determined by the anesthesiologists. Clinico-pathologic characteristics and survival outcomes of the patients were compared among the different co-morbidity groups. Results There were 1,792 (71.6%), 665 (26.6%), and 44 (1.8%) patients in ASA I, II, and III, respectively. Total 95 (3.8%) deaths and 269 (10.8%) recurrences (loco-regional and distant) occurred during the median follow-up period of 71 months. Patients with high comorbidity showed significantly higher rate of deaths (51 (2.8%), 38 (5.7%) and 6 (13.6%) deaths in ASA I, II and III group, respectively, p

Objective To evaluate the effects of the implementation of critical pathway (CP) in stroke patients treated at a single university hospital. Methods A retrospective medical review collected data from 497 patients who had suffered acute stroke in the rehabilitation center. Stroke outcomes were compared between before and after the implementation of CP based on factors including demographic factors, stroke characteristics, pre-existing medical conditions, medical complications, functional states, and length of stay (LOS). Results After the implementation of CP, the patients showed significantly higher stage for upper proximal (p=0.008) and lower extremity (p=0.001) on Brunnstrom stage and significantly lower scores for modified Rankin Scale (p=0.003) at transfer. For those with pre-existing medical conditions, there were significantly increased osteoarthritis (p=0.002) and valvular heart disease (p=0.011). Regarding medical complications during acute inpatient rehabilitation, there were significantly decreased shoulder pain (p=0.001) and dysphagia (p=0.017), and significantly increased gastrointestinal symptoms (p=0.001). Functional gain and efficiency of stroke patients during rehabilitation center hospitalization did not significantly change after implementation of CP. But, shorter LOS of total hospitalization, pre-rehabilitation center hospitalization, and rehabilitation center hospitalization were evident. Conclusion After the implementation of CP, patients less often developed complications and displayed no changes in functional gain and efficiency. They had shorter LOS of total hospitalization, pre-rehabilitation center hospitalization and rehabilitation center hospitalization.

Objective To evaluate the effect of extracorporeal shock wave therapy (ESWT) on lower limb spasticity in subacute stroke patients. Methods We studied thirty hemiplegic subacute stroke patients with ankle plantar flexor spasticity. ESWT was applied for 1 session/week, with a total of 3 sessions at the musculotendinous junction of medial and lateral gastrocnemius muscles. Patients were evaluated both clinically and biomechanically at baseline, after sham stimulation, and at immediately 1 week and 4 weeks after ESWT. For clinical assessment, Modified Ashworth Scale (MAS), clonus score, passive range of motion of ankle, and Fugl-Myer Assessment for the lower extremity were used. A biomechanical assessment of spasticity was conducted by an isokinetic dynamometer. Two parameters, peak eccentric torque (PET) and torque threshold angle (TTA), were analyzed at the velocities of 60°/sec, 180°/sec, and 240°/sec. Results After sham stimulation, there were no significant changes between each assessment. MAS and PET (180°/sec and 240°/sec) were significantly improved immediately and 1 week after ESWT. However, these changes were not significant at 4 weeks after ESWT. PET (60°/sec) and TTA (60°/sec, 180°/sec, and 240°/sec) were significantly improved immediately after ESWT. Yet, these changes were not significant at 1 week and 4 weeks after ESWT as well. Conclusion Lower limb spasticity in subacute stroke patients was significantly improved immediately after ESWT. Although the therapeutic effect of ESWT reduced with time and therefore was not significant at 4 weeks after ESWT, the degree of spasticity was lower than that of the baseline. Future studies with a larger sample of patients are warranted in order to verify the protocols which can optimize the effect of ESWT on spasticity.

Objective To assess the intra-rater and inter-rater reliability for measuring femoral anteversion angle (FAA) by a radiographic method using three-dimensional computed tomography reconstruction (3D-CT). Methods The study included 82 children who presented with intoeing gait. 3D-CT data taken between 2006 and 2014 were retrospectively reviewed. FAA was measured by 3D-CT. FAA is defined as the angle between the long axis of the femur neck and condylar axis of the distal femur. FAA measurement was performed twice at both lower extremities by each rater. The intra-rater and inter-rater reliability were calculated by intraclass correlation coefficient (ICC). Results One hundred and sixty-four lower limbs of 82 children (31 boys and 51 girls, 6.3±3.2 years old) were included. The ICCs of intra-rater measurement for the angle of femoral neck axis (NA) were 0.89 for rater A and 0.96 for rater B, and those of condylar axis (CA) were 0.99 for rater A and 0.99 for rater B, respectively. The ICC of inter-rater measurement for the angle of NA was 0.89 and that of CA was 0.92. By each rater, the ICCs of the intrarater measurement for FAA were 0.97 for rater A and 0.95 for rater B, respectively and the ICC of the inter-rater measurement for FAA was 0.89. Conclusion The 3D-CT measures for FAA are reliable within individual raters and between different raters. The 3D-CT measures of FAA can be a useful method for accurate diagnosis and follow-up of femoral anteversion.

Young breast cancer patients have a poorer prognosis, especially when their tumors are hormone receptor positive. We analyzed the association between Ki67 and age and the impact of these factors on outcomes in hormone receptor-positive breast cancer. The records of 9,321 hormone receptor-positive invasive breast cancer patients from three large centers were retrospectively reviewed. Each institution separately assayed Ki67 level immunohistochemically. Univariate and multivariate analysis for recurrence-free survival (RFS) was performed on 4,738 patients from a single center. Ki67 level was inversely proportional to age in all three data sets and was significantly higher for younger patients (p

Transforming growth factor (TGF) family is well known to induce the chondevrepogenic differentiation of mesenchymal stem cells (MSC). However, the precise signal transduction pathways and underlying factors are not well known. Thus the present study aims to evaluate the possible role of C2 domain in the chondevrepogenic differentiation of human mesenchymal stem cells. To this end, 145 C2 domains in the adenovirus were individually transfected to hMSC, and morphological changes were examined. Among 145 C2 domains, C2 domain of protein kinase C eta (PKCη) was selected as a possible chondevrepogenic differentiation factor for hMSC. To confirm this possibility, we treated TGFβ3, a well known chondevrepogenic differentiation factor of hMSC, and examined the increased-expression of glycosaminoglycan (GAG), collagen type II (COL II) as well as PKCη using PT-PCR, immunocytochemistry and Western blot analysis. To further evaluation of C2 domain of PKCη, we examined morphological changes, expressions of GAG and COL II after transfection of PKCη -C2 domain in hMSC. Overexpression of PKCη-C2 domain induced morphological change and increased GAG and COL II expressions. The present results demonstrate that PKCη involves in the TGF-β3-induced chondevrepogenic differentiation of hMSC, and C2 domain of PKCη has important role in this process.

Ziprasidone is a benzisothiazolyl piperazine derivative that was developed from the chemically related antipsychotic drug tiospirone, and it improves neurological functions of the ischemic brain and is effective in treatment of schizophrenia. Mesenchymal stem cells (MSCs) are considered as a leading candidate for neurological regenerative therapy because of their neural differentiation properties in damaged brain. We investigated whether the transplantation of neural progenitor cells (NPCs) derived from adipose mesenchymal stem cells combined with ziprasidone enhances neuroprotective effects in an animal model of focal cerebral ischemia. In combination therapy groups, significant reduction of infarct volume and improvement of neurological functions were observed at 3 days after middle cerebral artery occlusion (MCAO) compared with monotherapy. Co-administration of ziprasidone and NPCs enhanced the anti-apoptotic effect and reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with the NPCs alone group at 7 days after MCAO. Ziprasidone or the combination of ziprasidone and NPCs induced the expression of endogenous neurotrophic factor gene brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). The immunohistochemical investigation revealed that the ziprasidone and NPCs attenuated the increased intensity of microglial marker (Iba-1) in the infarcted cortical area. Moreover, the number of transplanted NPCs on day 7 with combination therapy was significantly higher than with NPCs alone. These effects might be responsible for improved functional behavior and increased survival of NPCs. Our finding indicates that combination therapy of ziprasidone and NPCs enhances neuroprotection against ischemic brain injury.

Objective To assess the intra-rater and inter-rater reliability for measuring tibial torsion measurements by a radiographic method using three-dimensional computed tomography reconstruction (3D-CT) and to compare the physical measures to those of 3D-CT. Method Th e study included 33 children who presented with intoeing gait. Tibial torsion was measured by 3D-CT. Distal reference point was the bimalleolar axis. Proximal reference points were the transtibial axis and posterior condylar axis. Physical measurements included thigh-foot angle (TFA) and bimalleolar angle (BMA). 3D-CT measurement and physical measurement were performed twice at both lower extremities by each rater. The intra-rater and inter-rater reliability were calculated by intraclass correlation coeffi ciency (ICC). Th e relationship between radiological and physical examination was calculated by Spearman correlation coeffi cient. Results Th e 3D-CT measures for tibial torsion were reliable within individual raters and between diff erent raters. However, physical measures for tibial torsion were reliable within an individual rater but not reliable between raters. The 3D-CT measures by any proximal reference axis were more reliable within a rater and between raters than physical measurements. Th ere was no signifi cant impact introduced by the selection of the proximal reference axis. Th e correlation coeffi ciency between 3D-CT and physical measurement methods was low. Conclusion Because the 3D-CT measurements for tibial torsion are more reliable than physical measurements, we recommend that accurate diagnosis of internal tibial torsion should be detected by using 3D-CT measurements. Also, considering the disadvantages of radiological measurements, physical measurement may be used for short term follow-up by same raters, as intra-rater reliability is relatively good.

It is not common for a patient who survives cardiac arrest to experience significant neurologic impairment such as acute and chronic post-hypoxic myoclonus, known as Lance-Adams syndrome. This syndrome is predominantly characterized by myoclonus that starts days to weeks after cardiopulmonary resuscitation in patients who regained consciousness. Although several cases of LAS were reported, the decisive treatment method has not been established. We report a 43 year old man with Lance-Adams syndrome who showed long-term improvement through treatment with anti-myoclonic agents and participation in a rehabilitation program.

Single-channel recordings of TASK-1 and TASK-3, members of two-pore domain K(+) channel family, have not yet been reported in dorsal root ganglion (DRG) neurons, even though their mRNA and activity in whole-cell currents have been detected in these neurons. Here, we report single-channel kinetics of the TASK-3-like K(+) channel in DRG neurons and up-regulation of TASK-3 mRNA expression in tissues isolated from animals with spinal cord injury (SCI). In DRG neurons, the single-channel conductance of TASK-3-like K(+) channel was 33.0+/-0.1 pS at -60 mV, and TASK-3 activity fell by 65+/-5% when the extracellular pH was changed from 7.3 to 6.3, indicating that the DRG K(+) channel is similar to cloned TASK-3 channel. TASK-3 mRNA and protein levels in brain, spinal cord, and DRG were significantly higher in injured animals than in sham-operated ones. These results indicate that TASK-3 channels are expressed and functional in DRG neurons and the expression level is up-regulated following SCI, and suggest that TASK-3 channel could act as a potential background K(+) channel under SCI-induced acidic condition.

Dorsal root ganglion (DRG) neurons express mRNAs for numerous two-pore domain K(+) (K(2P)) channels and G-protein coupled receptors (GPCR). Recent studies have shown that TRESK is a major background K(+) channel in DRG neurons. Here, we demonstrate the pharmacological properties of TRESK, including GPCR agonist-induced effects on DRG neurons. TRESK mRNA was highly expressed in DRG compared to brain and spinal cord. Similar to cloned TRESK, native TRESK was inhibited by acid and arachidonic acid (AA), but not zinc. Native TRESK was also activated by GPCR agonists such as acetylcholine, glutamate, and histamine. The glutamate-activated TRESK was blocked by lamotrigine in DRG neurons. In COS-7 cells transfected with mouse TRESK, 30 microM lamotrigine inhibited TRESK by approximately 50%. Since TRESK is target of modulation by acid, AA, GPCR agonists, and lamotrigine, it is likely to play an active role in the regulation of excitability in DRG neurons.

Peripheral neuropathy in burn patients may be frequently missed in clinical settings. Although its incidence has been reported, little is known regarding the factors that cause burn-related peripheral neuropathy. A retrospective chart review of the demographic and clinical characteristics of patients admitted to a university hospital based burn center was conducted to explore the characteristics of burn-related neuropathy and factors affecting its types or extent. The variables collected were gender, age, length of hospital stay, site and surface area of burn, type of burn, and electrodiagnostic findings. We found that flame injuries, and third degree injuries were the most common in patients with peripheral neuropathy. Axonotmesis was more common than demyelinating injury and polyneuropathy was more common than mononeuropathy. Higher degree and larger area burns were more frequently associated with axonotmesis than with demyelination. Length of hospital stay was significantly longer in patients with axonotmesis. Overall, more severe burns showed a significant association with axonotmesis and a tendency to be related to polyneuropathy.

We report here on the diffusion-weighted imaging of unusual white matter lesions in a case of Menkes disease. On the initial MR imaging, the white matter lesions were localized in the deep periventricular white matter in the absence of diffuse cortical atrophy. The lesion showed diffuse high signal on the diffusion-weighted images and diffuse progression and persistent hyperintensity on the follow up imaging. Our case suggests that the white matter lesion may precede diffuse cortical atrophy in a patient with Menkes disease.

Goals: Several cohort studies have reported inconsistent findings for the association between statin use and breast cancer recurrence. We investigated the effect of statin use on breast cancer recurrence using a meta-analysis of cohort studies. Methods: We searched MEDLINE (PubMed) and EMBASE in October 2014. Two evaluators independently reviewed and selected articles, based on pre-determined selection criteria. The primary endpoint was breast cancer recurrence, and the second endpoints were overall mortality and disease related mortality. Results: Out of 593 articles meeting our initial criteria, seven cohort studies (five for breast cancer recurrence and three for mortality) involving 77, 660 participants (13, 730 cases and 63, 930 controls) were included in the final analyses. In a fixed-effects meta-analysis of all the studies, breast cancer patients with statin use showed a decreased recurrence [hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.70–0.90, I = 0%], compared with those without statin use. In the subgroup meta-analysis, lipophilic statins reduced the recurrence of breast cancer (HR 0.75, 95%CI 0.64–0.87, I = 0%), whereas hydrophilic statins did not (HR 1.12, 95%CI 0.79–1.59, I = 0%). Also, the longer use of statins reduced breast cancer recurrence (HR 0.81, 95%CI 0.69–0.95, I = 0% for more than 2 years of medication). However, statins did not reduce mortality (HR 0.81, 95%CI 0.54–1.19, I = 87.5% in overall mortality; HR 0.73, 95%CI 0.46– 1.14, I = 82.8% in disease related mortality). Conclusion: The current meta-analysis showed that statin use reduced the recurrence of breast cancer. More prospective cohort studies and randomized controlled trials providing a higher level of evidence are needed. Disclosure of Interest: This work was supported by the National Cancer Center, Republic of Korea [National Cancer Center Grant NCC-1210102].

Purpose Neonatal late-onset hypocalcemia is defined as hypocalcemia developed after postnatal 3 days and associated with hypoparathyroidism, high phosphate diets and vitamin D deficiency. We experienced the increment of neonatal late onset hypocalcemia over 1 year. We tried to evaluate the relationship between late onset hypocalcemia and maternal hypovitaminosis D. Methods The medical records in the neonates with late-onset hypocalcemia during January 2007 to July 2008 were retrospectively reviewed. Among those patients, 17 paired sera of mothers and neonates had collected. The levels of 25-OH vitamin D (25OHD) and intact parathyroid hormone (iPTH) were measured and were compared with neonate and the mother. Results The mean gestational age was 38+1 weeks, and the mean body weight was 2,980 g. The onset time of hypocalcemia was 5.9 days of age. Most of them (88.2%) were feeding with formula and no one was only breast milk feeding. Of the 17 patients, 13 were born in spring or in winter. The median levels of calcium, phosphorus, alkaline phosphatase, iPTH and 25OHD were 7.0 mg/dL, 8.6 mg/dL, 191.0 U/L, 57.2 pg/mL and 24.0 ng/mL in neonates. The levels of 25OHD of 6 neonates were

Objective To examine the intra-rater, inter-rater, and inter-instrumental reliability of the digitalized pinch muscle strength dynamometer. Method Thirty normal subjects were examined for pinch strength, using both the Preston pinch gauge and the digitalized pinch dynamometer. The participants performed all pinch strength tests in the seated position as recommended by the American Society of Hand Therapists (ASHT). Three successive measurements were taken for each hand. The mean of the three trials was used for data analysis. The pinch strength tests performed used a repeated measure design and measurements were taken by each rater. Results The relationship between the Preston pinch gauge and the digitalized pinch dynamometer in pinch strength was reliable (the ICC were 0.821 and 0.785 in rater 1 and rater 2 respectively). The relationship between the first session and second session in pinch strength using the digitalized pinch dynamometer was reliable (the ICC were 0.872 and 0.886 in rater A and rater B respectively). The relationship between rater A and rater B in pinch strength using the digitalized pinch dynamometer was reliable (the ICC was 0.754). Conclusion The pinch strength measurement using the digitalized pinch dynamometer is reliable within the rater and between raters. Thus, the Preston pinch gauge and the digitalized dynamometer measure grip strength equivalently, and can be used interchangeably.