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Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.

We propose a neuronal network model which undergoes a saddle-node bifurcation on an invariant circle as the mechanism of the transition from the interictal to the ictal (seizure) state. In the vicinity of this transition, the model captures important dynamical features of both interictal and ictal states. We study the nature of interictal spikes and early warnings of the transition predicted by this model. We further demonstrate that recurrent seizures emerge due to the interaction between two networks., Comment: 9 pages, 7 figures

Although the internet is helpful and considered a preferred channel to get health information, some vulnerable populations such as the elderly have a digital divide. The purpose of this study was to test the development and intervention of the eHealth program based on the Information-Motivation-Behavioral Skills (IMB) model for improving internet health information seeking, understanding and utilization behaviors in the elderly. This study was a single group pretest-posttest design, and the eleven elderly aged 67-87 (mean74.6, SD 6.9) participated in 5 session program at a senior welfare center from 25 January to 22 February 2019. Each theory-based constructs of IMB model such as computer/web knowledge (p

Background Recently, palbociclib plus exemestane with GnRH agonist demonstrated a statistically significant improvement in progression-free survival (PFS) compared with that of the capecitabine for premenopausal women with hormone receptor-positive metastatic breast cancer (median PFS 20·1 vs. 14·4 months, p = 0·0235 ; HR 0·659 [95% C.I. 0·437–0·994])(Park YH et al, J Clin Oncol 37, 2019 [suppl; abstr 1007]). We evaluated PROs in YoungPEARL phase ll trial. Methods Pts (N = 189) were randomized 1:1 to receive palbociclib plus exemestane with GnRH agonist or capecitabine. PROs were assessed at day 1 (baseline), every 6 weeks, and at the end of treatment, using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30). Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between the treatment groups while controlling for baseline. Results Questionnaire completion rates were 100% at baseline and during treatment from baseline to 84 weeks in each group. Global health status/QoL scores were maintained from baseline to the end of treatment across all time points within each cohort. Between-treatment comparison in the change from baseline functioning scale scores showed trends favoring palbociclib arm for physical functioning (0.12 vs -3.66, p = 0.1201) while favoring capecitabine arm for emotional (0.87 vs 2.61, p = 0.5963) and social functioning (2.63 vs 5.97, p = 0.3234). There was a trend to improve appetite loss (-5.27 vs 0.72, p = 0.1484) and insomnia tended to get worse (3.81 vs -2.65, p = 0.0736) in palbociclib arm while capecitabine arm showed the greater improvement in pain (-2.80 vs -5.83, p = 0.3200) but worsening in diarrhea (1.17 vs 7.37, p = 0.0598) without statistical significance. Conclusions These findings show that palbociclib plus endocrine therapy maintained high PRO scores with some different function and symptom profiles compared with capecitabine arm. Clinical trial identification NCT02592746. Legal entity responsible for the study Korea Cancer Study Group. Funding Pfizer. Disclosure All authors have declared no conflicts of interest.

1007 Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor(HR)-positive, HER2-negative metastatic breast cancer(MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines based on endocrine resistance and/or on physician’s concern of worse prognosis associated with aggressive tumor behavior and younger age. In terms of the chemotherapy regimens, capecitabine seems one of the most popular options. The purpose of this phase II study is to assess the safety and the clinical anti-tumor activity of exemestane plus GNRH agonist in combination with palbociclib versus capecitabine in premenopausal HR-positive MBC patients. Methods: This is a prospective, two-arm, randomized, multi-center open-label phase II study of the Korean Cancer Study Group. Patients were allowed with previous 1 line of chemotherapy for MBC. De Novo metastatic patients should have been treated with tamoxifen before enrollment. Patients were randomized to chemotherapy (capecitabine 1250 ㎎/㎡twice a day from day 1 to 14 every 3 weeks) or endocrine therapy combination (exemestane 25 mg for 28 days and palbociclib 125 mg for 21 days every 4 weeks with GNRH agoinst). Primary endpoint was Progression-Free Survival (PFS). Results: Among 189 patients enrolled between 2016 and 2018 from 14 centers, 184 patients were randomly assigned to chemotherapy (n = 92) or endocrine therapy with palbociclib (n = 92). Median age was 44 (range 28-58). De Novo MBC was found equally in both arm (30%). During median 14 months of follow-up, median PFS was superior in endocrine with palbociclib than in capecitabine arm [19.0 vs. 11.3 months, p = 0.0493 by log-rank test; Hazard Ratio (HR) 0.643 (0.415-0.999), p = 0.0493]. Approximately half of the patients (51%) were treatment naïve in the advanced setting (49% for palbociclib vs. 51% for capecitabine). Grade III or more hematologic toxicities were more common in palbociclib than in capecitabine with statistical significance (60.9% vs. 19.2%, p < 0.0001). Diarrhea (11% vs. 38%) and Hand-Foot syndromes (1% vs. 76%) were more common in capecitabine arm. Conclusions: Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in patients with premenopausal ER-positive MBC. Clinical trial information: NCT02592746.

e15553 Background: Gastric cancer, a highly aggressive malignancy, frequently recurs despite curative surgery and metastasizes to lymph node and distant sites. Epithelial-mesenchymal transition (EMT) is the main phenomenon of cancer progression, including invasion and metastasis. It is regulated by crosstalks between diverse intracellular signaling pathways such as Wnt/β-catenin and phosphatidylinositol-3-kinase(PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways. Here, this study elucidated the effects of co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways on gastric cancer. Methods: It is known that Wnt/β-catenin signaling pathways are constitutively activated in two of gastric cancer cell lines, AGS and MKN-28. ICG-001 (β-catenin transcription inhibitor) and rapamycin (mTOR inhibitor) were used for dual blockade, and then the combinatory effects were examined. Results: As a result, both cell lines were significantly affected by the β-catenin transcription inhibitor, ICG-001, and addition of the mTOR inhibitor, rapamycin induced marginal inhibitory effects on cancer cell proliferation and target gene expression. In addition, invasive activity was 62.3 ± 15.7% and 53 ± 14.4% inhibited by single treatment, but it was 79 ± 13.3% inhibited by co-treatment. Moreover, migratory activity was 33 ± 13%, 42 ± 9% inhibited by single treatment, but it was 82 ± 4% by co-treatment. Interestingly, Snail, one of the important regulatory protein during EMT process, was significantly decreased by co-treatment. Conclusions: Taken together, these results suggest that co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways could effectively enhance antitumor effects on gastric cancer via the inhibition of invasion and migration as well as decrease of Snail expression.

e15544 Background: Gastric cancer is characterized by a high rate of relapse and failure of chemotherapy because of the emergence of drug resistant cells. Hence, resistance to chemotherapy is a major obstacle for the management of gastric cancer. It might be related with the development of cancer stem cells (CSCs). The aim of this study is to investigate the characteristics of the 5-fluorouracil (FU) resistant gastric cancer and to study how to restore the chemosensitivity. Methods: We used the AGS gastric cancer cell line (AGS) and transformed it into a 5-FU resistant cell line (AGS-R). AGS-R was established by continuous exposure of the cells to progressively increasing concentrations of 5-FU for about 1 year and modulating mRNA expression levels of four genes associated with thymidylate synthase (TS). The research methods used were MTT assay, flow cytometry analysis, luciferase reporter assay, western blotting, and siRNA transfection. Results: 5-FU-resistant gastric cancer cell, AGS-R was established by continuous exposure to 5-FU with gradual increase of its concentration for about 1 year. Comparing with AGS, thymidylate synthase (TS) expression in AGS-R was highly increase at transcriptional and translational level. And decreased transcriptional activity of β-catenin in AGS-R was confirmed by Western blotting and luciferase assay. Even though treatment with ICG-001, an inhibitor of β-catenin, showed growth inhibition of AGS in a dose- and time-dependent manner, but it could not in AGS-R. The expression of CD44, well-known CSCs marker, was significantly higher on AGS-R compared to AGS. And the Notch pathway was remarkably up-regulated. Flow cytometry analysis revealed that CD44 expression was reduced on AGS-R transfected with specific siRNA for notch intracellular domain (NICD). Conclusions: This study suggests that chemoresistance of gastric cancer against continuous exposure to 5-FU is associated with decrease of β-catenin activity and development of stemness via the activation of Notch pathway. Therefore, the inhibition of Notch pathway might be a potential therapeutic target in 5-FU-resistant gastric cancer.

The aims of this study were to investigate the correlation between topoisomerase II alpha (TOP2A), microtubule-associated protein-tau (MAP-tau) and other prognostic factors in breast cancer and to evaluate the predictive value of TOP2A and MAP-tau in breast cancer patients who received anthracycline and taxane-containing adjuvant chemotherapy.Seventy patients with axillary lymph node positive breast cancer who underwent curative surgery between January 2000 and December 2005 were evaluated retrospectively. The levels of protein expression of TOP2A and MAP-tau were assessed using immunohistochemistry.Among the 70 patients, 43 (61.4%) showed TOP2A overexpression and 30 (42.9%) showed MAP-tau positivity. TOP2A overexpression was associated with p53 positivity and high histological grade. MAP-tau positivity was associated with a lower positive lymph node ratio, lower proliferative activity, and hormone receptor positivity. Based on the TOP2A and MAP-tau expression, there was no significant difference in disease-free survival in the breast cancer patients who received anthracycline and taxane-containing adjuvant chemotherapy.We conclude that immunohistochemical analysis of TOP2A and MAP-tau protein expression may not predict the benefits of adjuvant anthracycline and taxane chemotherapy in axillary node positive breast cancer.

OBJECTIVE: To explore the lived experience of Korean first-time immigrant mothers giving birth in the United States from their own perspectives.DESIGN: Hermeneutic phenomenological study using semistructured interviews with seven Korean first-time mothers who recently gave birth in the United States. The interview data were analyzed to identify emerging themes, which were centered on both positive and negative perceptions of the experience.RESULTS: The emerged positive perceptions included friendly health care providers, husband’s active involvement, strengthened bonding with husband, freedom from traditional rituals and taboos, and giving the baby a U.S. citizenship. Difficulty in making medical decisions, health literacy, a different health system, different postpartum food culture, and lack of support system were identified as negative perceptions.CONCLUSIONS: The findings of this study may help health care providers in obstetrical settings better understand the meaningful aspects of childbirth experienced by Korean immigrant first-time mothers while they gave birth and received perinatal care in the U.S. sociocultural context. Immigrants’ childbirth experience in a foreign country has multidimensional aspects that suggest further research on their perinatal health needs evolving from a different health culture, culturally embedded health practices, and lack of support system.

Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC.This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used.The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events.Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society.

Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa®) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.

Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia remain poorly understood. Here, we demonstrate an oncogenic Kras(G12D)-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of Kras(G12D)-PDECs, and, consistent with the role of GM-CSF in Gr1(+)CD11b(+) mobilization, this effect is mediated by CD8(+) T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity.

Hypoxia, a condition of insufficient oxygen availability, occurs during normal development as well as tumorigenesis. Cellular responses to hypoxia are primarily mediated by hypoxia-inducible factors (HIFs). Recent studies have revealed that dormant hematopoietic stem cells (HSCs) reside within hypoxic regions of the bone marrow and that HIF is a critical player in HSC homeostasis. The functional significance of HIF in maintaining stemness also applies to cancer stem cells in hematological malignancies. These findings indicate that better understanding of the mechanisms underlying HIF functions in stem cells should permit the development of new therapies for tissue regeneration and cancer.

Purposes: Most medical schools in Korea do not provide adequate education in end-of-life care. This study was designed to illustrate the need to improve end-of-life care edu cation and to assess the effect of the education on fourth-year medical students’ awareness and attitude towards hospice and palliative care for terminally ill patients. Methods: One hundred sixty six fourth-year medical students were surveyed with questionnaires on end-of-life care before and after they received the education. Results: Before receiving the education, students most frequently answered “ at the end of life” (33.6%) was appropriate time to write an advance medical directive. After the education, the most frequent answer was “ in healthy status” (58.7%). More students agreed to withholding or withdrawing futile life-sustaining treatment increased after the education (48.1% vs. 92.5% (P＜0.001) for cardiopulmonary resuscitation, 38.3% vs. 92.5% (P＜0.001) for intubation and mechanical ventilation, 39.1% vs. 85.8% (P＜ 0.001) for inotropics, 60.9% vs. 94.8% (P＜ 0.001) for dialysis and 27.8% vs. 56.0% (P＜0.001) for total parenteral nutrition). Significantly more students opposed euthanasia after the education (46.6% vs. 82.1%, P＜0.001). All students agreed to the need for education in end-of-life care. Conclusion: After reflecting on the meaning of death through the end-of-life care education, most s tudents recognized the need for the education. The education brought remarkable changes in students’ awareness and attitude towards patients at the end of life. We suggest end-of-life care education should be included in the regular curriculum of all medical schools in Korea. (Korean J Hosp Palliat Care 2012;15:30-35)

The purpose of this study was to prospectively evaluate interobserver agreement on lesion detection and characterization in the review of automated ultrasound images of the breast by five radiologists.From August to October 2009, bilateral whole-breast ultrasound examinations were performed with an automated technique and with a handheld device for 55 women consecutively scheduled to undergo diagnostic ultrasound. Three-dimensional volume data from automated ultrasound were reviewed by five radiologists, who were unaware of the results of ultrasound with a handheld device and mammography and of the clinical information. If a lesion was detected with automated ultrasound, clock-face position, distance from the nipple, largest diameter, and BI-RADS final assessment category were evaluated. If the lesion was a mass, shape, orientation, margin, echogenicity, and posterior feature were analyzed. Intraclass correlation coefficients and kappa statistics were used for statistical analysis.At least two observers identified 145 lesions with automated ultrasound. Among 725 possible detections, 587 (81%) detections were made. Individual investigators detected between 74% (107/145) and 88% (127/145) of the lesions. The rate of detection of lesions larger than 1.2 cm was 92%. Most lesions detected only with handheld ultrasound (11/12, 92%) or automated ultrasound (34/36, 94%) were cysts or probably benign masses. All intraclass correlation coefficients for lesion location and size exceeded 0.75, indicating high reliability. Substantial agreement was found for mass shape (κ = 0.71), orientation (κ = 0.72), margin (κ = 0.61), and BI-RADS final assessment category (κ = 0.63).Detection of lesions larger than 1.2 cm in greatest diameter was reliable. High reliability was obtained for reporting lesion size and location. Substantial agreement was obtained for description of key feature and final assessment category.

신생아의 태반을 통한 사람면역결핍바이러스 감염은 아프리카에서 흔하지만, 대한민국에서는 아직 보고된 적이 없다. 대한민국에서 사람면역결핍바이러스 감염자의 수는 증가하는 추세이며, 특히 생식연령에서의 사람면역결핍바이러스 감염자의 수가 증가하고 있다. 이는 사람면역결핍바이러스 수직 감염의 위험성을 높인다. 저자들은 아직 국내에 보고되지 않은 자궁 내 전파를 통한 신생아의 사람면역결핍바이러스 감염을 경험하였기에 보고하는 바이다. 자궁 내 전파를 통한 사람면역결핍바이러스 감염의 예후는 좋지 않으나 본 증례의 남아는 생후 9개월 경까지 정상 성장과 발달을 보였으며 특별한 의학적 문제가 없었다.

Squamous cell carcinoma of the breast and its subtype, basal-human epidermal growth factor receptor 2 (HER2) phenotype, are very rare. Herein, we report a patient who developed recurrence of squamous cell carcinoma of the breast with basal-HER2 subtype 6 years after the initial diagnosis of invasive ductal carcinoma of the HER2 subtype. To the best of our knowledge, recurrence of invasive ductal carcinoma in the form of metaplastic squamous cell carcinoma of basal-HER2 subtype has not been reported previously. We present a pathological perspective of our experience.

Central venous catheterization is a routinely performed procedure in clinical practice. While cerebral air embolism after the removal of the central venous catheter is very rare, it is one of the most serious complications that can lead to fatal outcomes. In this report, we present a rare case of a cerebral air embolism after the removal of the central venous catheter in a patient with a patent foramen ovale.

Amphiphilic α-tocopherol oligochitosan conjugates were constructed by conjugating α-tocopherol succinate to water soluble oligochitosans with various molecular weights. In aqueous medium, the tocopherol oligochitosan conjugates self-assembled to single layered oligomersomes. The sizes of α-tocopherol-oligochitosan-based oligomersomes (TCOsomes) could be controlled by chain lengths of oligochitosans. The mean sizes of TCOsomes were 220 and 377 nm as the sizes of oligochitosans were 4000 and 12,500, respectively. For all TCOsomes formed in this study, polydispersity indexes were in the ranges of 0.111-0.256. Cryo-TEM images showed clear thickening in the unilamellar layer of TCOsomes upon complexation with siRNAs. Zeta potentials decreased as the ratios of siRNA/TCOsomes increased. TCOsomes self-assembled from tocopherol-oligochitosan 4K (TCOsome(4K)) significantly enhanced the cellular uptake of siRNAs (>98%), and reduced the expression of target proteins more effectively than did Lipofectamine 2000. In tumor xenografted mice, the intratumoral administration of siMcl-1 using TCOsomes substantially silenced the expression of Mcl-1 and prevented the growth of tumor. The hematoxylin-eosin staining showed the apoptosis of cells in the tissues of the mice treated with siMcl-1/TCOsome(4K) complexes, but not with siGL2/TCOsome(4K) complexes. The self-assembling and size-controllable oligomersomes might be suitable for effective in vivo delivery of siRNAs.

Backgrounds : Autophagy plays an important role in the pathogenesis of multiple myeloma. Autophagy usually acts on a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death and could synergize with proteasome inhibitors in myeloma cells. In this study, we investigated the synergistic mechanism of apoptosis with bortezomib (BTZ) and autophagy inhibitors in the MM cells. Methods : We evaluated the change of autophagy, apoptosis, mitochondrial ROS and cellular level of redox enzymes, including peroxiredoxin (Prx), thioredoxin (Trx), thioredoxin reductase (Trx-R) using human myeloma cell lines, MM.1S and MM.1R during BTZ treatment. To study the status of oxidation for redox enzyme, sulfinic acid (SO2) or multimeric form of Prx, Trx and Trx-R by western blot were measured using non-reducing or reducing gel. Results : Mitochondrial over cytosolic ROS of MM cells was increased significantly after 24 hour of BTZ (2.5 nM) treatment. Apoptosis of MM cell after BTZ treatment was increased in concordance with mitochondrial ROS increment of MM cells. N-acetylcystein (NAC) reversed BTZ-induced mitochondrial ROS elevation and apoptosis of MM cells as well. Increased expressions of cleaved caspase-9 and cleaved caspase-3 were also observed during BTZ-induced MM cell apoptosis. LC3-II expression was elevated along with increment of mitochondrial ROS and apoptosis of MM cells after BTZ treatment. Oxidation of PRX4 and TRX2 was observed during BTZ-induced apoptosis of MM cells. After treatment of NAC, LC3-II and PRX4/TRX2 expression was reversed. Inhibition of autophagy with 3-Methyladenine (3-MA) not only resulted in a further increase in BTZ-induced apoptosis but also induced mitochondrial ROS in MM cells. Conclusions : Autophagy is induced during BTZ treatment in MM cells. Our experiment showed crosstalk between autophagy and mitochondrial ROS and its redox enzymes during BTZ-induced MM cell apoptosis. Inhibition of autophagy with 3-MA potentiates BTZ-induced apoptosis of MM cells via up regulation of mitochondrial ROS. Our results provide new perspective on the cellular mechanism of action of BTZ and support the synergism of BTZ with autophagy inhibitor for an improved therapy of the multiple myeloma. Disclosures No relevant conflicts of interest to declare.

e18015Background: Over- or under expression of mRNA result from genetic alteration. mRNA expression based pathway are as important as single gene level mutations analyzed by next generation sequenc...

We considered a Bak–Sneppen model on a Sierpinski gasket fractal. We calculated the avalanche size distribution and the distribution of distances between subsequent minimal sites. To observe the temporal correlations of the avalanche, we estimated the return time distribution, the first-return time, and the all-return time distribution. The avalanche size distribution follows the power law, P ( s ) ∼ s − τ , with the exponent τ = 1.004 ( 7 ) . The distribution of jumping sites also follows the power law, P ( r ) ∼ r − π , with the critical exponent π = 4.12 ( 4 ) . We observe the periodic oscillation of the distribution of the jumping distances which originated from the jumps of the level when the minimal site crosses the stage of the fractal. The first-return time distribution shows the power law, P f ( t ) ∼ t − τ f , with the critical exponent τ f = 1.418 ( 7 ) . The all-return time distribution is also characterized by the power law, P a ( t ) ∼ t − τ a , with the exponent τ a = 0.522 ( 4 ) . The exponents of the return time satisfy the scaling relation τ f + τ a = 2 for τ f ⩽ 2 .

We study the critical properties of the Bak–Sneppen coevolution model on scale-free networks by Monte Carlo method. We report the distribution of the avalanche size and fractal activity through the branching process. We observe that the critical fitness fc(N) depends on the number of the node such as fc(N) ~ 1/ log (N) for both the scale-free network and the directed scale-free network. Near the critical fitness many physical quantities show power-law behaviors. The probability distribution P(s) of the avalanche size at the critical fitness shows a power-law like P(s) ~ s-τ with τ = 1.53(5) regardless of the scale-free network and the directed scale free network. The probability distribution Pf(t) of the first return time also shows a power-law such as Pf(t) ~ t-τf. The critical exponents τf are equivalent for both the scale-free network and the directed scale-free network. We obtain the critical exponents as τf = 1.776(5) at the scalinge regime. The directionality of the network does not change the universality on the network.

We consider the probability distribution function of the trading volume and the volume changes in the Korean stock market. The probability distribution function of the trading volume shows double peaks and follows a power law, P ( V / 〈 V 〉 ) ∼ ( V / 〈 V 〉 ) − α at the tail part of the distribution with α = 4.15 ( 4 ) for the KOSPI (Korea composite Stock Price Index) and α = 4.22 ( 2 ) for the KOSDAQ (Korea Securities Dealers Automated Quotations), where V is the trading volume and 〈 V 〉 is the monthly average value of the trading volume. The second peaks originate from the increasing trends of the average volume. The probability distribution function of the volume changes also follows a power law, P ( V r ) ∼ V r − β , where V r = V ( t ) − V ( t − T ) and T is a time lag. The exponents β depend on the time lag T . We observe that the exponents β for the KOSDAQ are larger than those for the KOSPI.

This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer.We enrolled 63 patients who received capecitabine 830 mg/m(2) orally twice daily on days 1-21 plus gemcitabine 1000 mg/m(2) as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles.A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13-34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5-5.7) and 7.5 months (95% CI 5.0-10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand-foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent.The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.

We analyzed the publicly available ChromHMM BED files of the ENCODE project and tested the Markov properties of the different chromatin states in the human genome. Nucleotide frequency profiles of regional chromatin segmentations were analyzed, and Markov chains were built to detect Markov properties in the chromatin states of different ChromHMM regions. By estimating the transition probabilities of 200-base pair nucleotide sequences of the human genome, we constructed a nucleotide-sequence-based Markovian chromatin map called SeqChromMM.

Background The β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER) and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer. Methods We established tamoxifen-resistant (TamR) cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay. Results TamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells. Conclusion These results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.

Recent advances in computational epigenetics have provided new opportunities to evaluate n-gram probabilistic language models. In this paper, we describe a systematic genome-wide approach for predicting functional roles in inactive chromatin regions by using a sequence-based Markovian chromatin map of the human genome. We demonstrate that Markov chains of sequences can be used as a precursor to predict functional roles in heterochromatin regions and provide an example comparing two publicly available chromatin annotations of large-scale epigenomics projects: ENCODE project consortium and Roadmap Epigenomics consortium.

We consider the probability distribution function (pdf) and the multiscaling properties of the index and the traded volume in the Korean stock market. We observed the power law of the pdf at the fat tail region for the return, volatility, the traded volume, and changes of the traded volume. We also investigate the multifractality in the Korean stock market. We consider the multifractality by the detrended fluctuation analysis (MFDFA). We observed the multiscaling behaviors for index, return, traded volume, and the changes of the traded volume. We apply MFDFA method for the randomly shuffled time series to observe the effects of the autocorrelations. The multifractality is strongly originated from the long time correlations of the time series.

We report the quiet-time probability distribution of the absolute return in the Korean stock-market index. We define the quiet time as a time interval during the absolute return of the stock index that are above a threshold r c . Through an exponential bin plot, we observe that the quiet-time distribution (qtd) shows power-law behavior, p f ( t ) ∼ t - β , for a range of threshold values. The quiet-time distribution has two scaling regimes, separated by the crossover time t c ≈ 200 min . The power-law exponents of the quiet-time distribution decrease when the return time Δ t increases. In the late-time regime, t > t c , the power-law exponents are independent of the threshold within the error bars for the fixed return time. The scaled qtd is characterized by a scaling function such as p f ( t ) ∼ ( 1 / T ) f ( t / T ) where the scaling function f ( x ) ∼ x - β 2 and T is the average quiet time. The scaling exponents β 2 depend on the return time Δ t and are independent of the threshold r c . The average quiet time follows the power law such as T ∼ r c δ where the exponents δ depend on the return time Δ t .

Inhibitors of tumor necrosis factor-alpha (TNF-alpha) have been approved for treating rheumatoid arthritis. As one of the biological response modifiers, etanercept has also been used in the treatment of psoriatic arthritis and inflammatory bowel disease. While etanercept is effective, certain infectious complications, such as tuberculosis, fungus, and cytomegalovirus, have been reported. We report the first Korean case of adenoviral pneumonia in a 55-year-old female who developed disseminated adenoviral infection following etanercept treatment, which resolved after anti-TNF-alpha discontinuation.

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous KrasG12D-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC. Surprisingly, pancreas-specific Hif1a deletion drastically accelerated KrasG12D-driven pancreatic neoplasia and was accompanied by significant increases in intrapancreatic B lymphocytes, featuring prominent influx of a rare “B1b” B-cell subtype. Finally, treatment of HIF1α-deficient mice with B cell–depleting αCD20 monoclonal antibodies inhibited progression of pancreatic intraepithelial neoplasia (PanIN). Our data reveal a previously unrecognized role for B cells in promoting pancreatic tumorigenesis and implicate HIF1α as a critical regulator of PDAC development. Significance: We show here that pancreas-specific Hif1a deletion promotes PDAC initiation, coincident with increased intrapancreatic accumulation of B cells, and that B-cell depletion suppresses pancreatic tumorigenesis. We therefore demonstrate a protective role for HIF1α in pancreatic cancer initiation and uncover a previously unrecognized function of B cells. Cancer Discov; 6(3); 256–69. ©2015 AACR. See related commentary by Roghanian et al., p. 230. See related article by Pylayeva-Gupta et al., p. 247. See related article by Gunderson et al., p. 270. This article is highlighted in the In This Issue feature, p. 217

We present the theory of the k-core pruning process (progressive removal of nodes with degree less than k) in uncorrelated random networks. We derive exact equations describing this process and the evolution of the network structure, and solve them numerically and, in the critical regime of the process, analytically. We show that the pruning process exhibits three different behaviors depending on whether the mean degree of the initial network is above, equal to, or below the threshold _c corresponding to the emergence of the giant k-core. We find that above the threshold the network relaxes exponentially to the k-core. The system manifests the phenomenon known as "critical slowing down", as the relaxation time diverges when tends to _c. At the threshold, the dynamics become critical characterized by a power-law relaxation (1/t^2). Below the threshold, a long-lasting transient process (a "plateau" stage) occurs. This transient process ends with a collapse in which the entire network disappears completely. The duration of the process diverges when tends to _c. We show that the critical dynamics of the pruning are determined by branching processes of spreading damage. Clusters of nodes of degree exactly k are the evolving substrate for these branching processes. Our theory completely describes this branching cascade of damage in uncorrelated networks by providing the time dependent distribution function of branching. These theoretical results are supported by our simulations of the $k$-core pruning in Erdos-Renyi graphs., Comment: 12 pages, 10 figures

We study a simple model for a neuron function in a collective brain system. The neural network is composed of an uncorrelated configuration model (UCM) for eliminating the degree correlation of dynamical processes. The interaction of neurons is assumed to be isotropic and idealized. These neuron dynamics are similar to biological evolution in extremal dynamics with locally isotropic interaction but has a different time scale. The functioning of neurons takes place as punctuated patterns based on avalanche dynamics. In our model, the avalanche dynamics of neurons exhibit self-organized criticality which shows power-law behavior of the avalanche sizes. For a given network, the avalanche dynamic behavior is not changed with different degree exponents of networks, γ≥2.4 and various refractory periods referred to the memory effect, Tr. Furthermore, the avalanche size distributions exhibit power-law behavior in a single scaling region in contrast to other networks. However, return time distributions displaying spatiotemporal complexity have three characteristic time scaling regimes Thus, we find that UCM may be inefficient for holding a memory.

Background In this study we explored the effectiveness of adjuvant chemotherapy in node-positive, resected thoracic esophageal squamous cell carcinoma patients. Methods A prospective study of postoperative chemotherapy in N1 esophageal cancer patients who received curative resection was conducted and compared with the historical control group in regard to recurrence rate, patterns of failure, disease-free survival rate, and overall survival rate. The postoperative chemotherapy consisted of cisplatin (60 mg/m2 intravenously) and 5-fluorouracil (1,000 mg/m2 per day) in a continuous infusion for 4 days. Three cycles were administered at 3-week intervals. Results Forty patients were accrued from January 1998 to January 2003 at Samsung Medical Center for adjuvant chemotherapy. The historical control group consisted of 52 patients who received curative resection but not adjuvant chemotherapy during the same period of time. The 3-year disease-free survival rate was 47.6% in the adjuvant group and 35.6% in the control group (p = 0.049). The estimated 5-year overall survival rates were 50.7% in the adjuvant group and 43.7% in the control group (p = 0.228). The significant predictive factors for tumor recurrence were the number of positive lymph nodes (p = 0.008) and the adjuvant chemotherapy (p = 0.030). Conclusions This study suggests that the postoperative chemotherapy may prolong disease-free survival in lymph node-positive, curatively resected esophageal cancer patients. The postoperative treatment modality for esophageal cancer patients should be determined according to the lymph node status and a randomized phase III clinical trial is warranted using adjuvant chemotherapy if the esophageal cancer is lymph node-positive.

Purpose Cancer clinical trials in Korea have rapidly progressed in terms of quantity and quality during the last decade. This study evaluates the current status of cancer clinical trials in Korea and their associated problems. Materials and methods We analyzed the clinical trials approved by the Korea Food and Drug Administration (KFDA) between 2007 and 2013. A nationwide on-line survey containing 22 questions was also performed with several cooperative study groups and individual researchers in 56 academic hospitals. Results The number of cancer clinical trials approved by the KFDA increased almost twofold from 2007 to 2013. The number of sponsor-initiated clinical trials (SITs) increased by 50% and investigator-initiated clinical trials (IITs) increased by almost 640%. Three hundred and forty-four clinical trials were approved by the KFDA between 2012 and 2013. At the time of the on-line survey (August 2013), 646 SITs and 519 IITs were ongoing in all hospitals. Six high volume hospitals were each conducting more than 50 clinical trials, including both SITs and IITs. Fifty-six investigators (31%) complained of the difficulties in raising funds to conduct clinical trials. Conclusion The number of cancer clinical trials in Korea rapidly increased from 2007 to 2013, as has the number of multicenter clinical trials and IITs run by cooperative study groups. Limited funding for IIT is a serious problem, and more financial support is needed both from government agencies and public donations from non-profit organizations.

The first Korean Breast Cancer Treatment Consensus Conference Expert Panel reviewed and endorsed new evidence on aspects of local and regional therapies and diagnostic procedures that support the conservative application of results from recent clinical trials. This conference clarified the barriers that limit the application of recent clinical trial results, such as questions about level of evidence, differences between the setting of clinical trials and that of daily clinical practice, and medical necessities and environment. Detailed decisions recommended for the treatment and diagnosis, according to the from the consensus conference, are recorded including details of the votes. These recommendations differed in the degree of support for clinical consideration of disease extent and host factors, medical necessities, and environment.

We find that sensory noise delivered together with a weak periodic signal not only enhances nonlinear response of neuronal networks, but also improves the synchronization of the response to the signal. We reveal this phenomenon in neuronal networks that are in a dynamical state near a saddle-node bifurcation corresponding to appearance of sustained network oscillations. In this state, even a weak periodic signal can evoke sharp nonlinear oscillations of neuronal activity. These sharp network oscillations have a deterministic form and amplitude determined by nonlinear dynamical equations. The signal-to-noise ratio reaches a maximum at an optimum level of sensory noise, manifesting stochastic resonance (SR) at the population level. We demonstrate SR by use of simulations and numerical integration of rate equations in a cortical model with stochastic neurons. Using this model, we mimic the experiments of Gluckman et al. [B. J. Gluckman et al, Phys. Rev. Lett., v. 77, 4098 (1996)] that have given evidence of SR in mammalian brain. We also study neuronal networks in which neurons are grouped in modules and every module works in the regime of SR. We find that even a few modules can strongly enhance the reliability of signal detection in comparison with the case when a modular organization is absent., Comment: 10 pages, 8 figures

Those living in rural areas face particular risks to health and well-being as they are more likely to be poor, have no health insurance, and have less access to health care. Many obstacles exist in achieving optimal rural health outcomes. Many of the health related issues experienced by adolescents are preventable and are often related to risky behavior such as substance use and abuse, smoking, and unprotected sex. The purpose of this review is to define the current primary health concerns of rural dwelling adolescents worldwide. Based on current research, the primary health related problems of rural adolescents were identified as risky sexual behaviors, mental health issues, violence and bullying, substance and alcohol use, and overweight and obesity. These problems are exacerbated by diminished access to care, peer influences, and parental influences. This integrative review also illustrates many dimensions of health disparities exist in rural areas. When addressing diversity in care models, it is important to consider the rural setting as well as race or ethnicity, sex, and socioeconomic status in designing curriculum and interventions. Globally, evidence based findings are needed to inform curriculum and respond to the health needs of rural adolescents. Health Concerns of Rural Dwelling Adolescents Vol. 9, Issue 1 (2014) 2 Programs and rural initiatives for adolescents can decrease the prevalence of established health problems and lower health care expenditures across life spans. Those living in rural areas face particular risks to health and well-being (United States [U.S.] Department of Health and Human Services [HHS], 2011). Rural dwellers are more likely than their urban counterparts to be poor, have no health insurance, and have less access to health care (Gamm, Hutchinson, Dabney, & Dorsey, 2003; Ziller, Anderson, & Coburn, 2010). Rural health concerns continue to draw attention from policy makers, clinicians and researchers. Healthy People 2020 re-emphasized the 2010 goal to address the health needs among rural U.S. populations (Bolin & Gamm, 2003; HHS, Healthy People 2020, 2011). Nonetheless, many obstacles exist in achieving optimal rural health outcomes. The purpose of this article is to synthesize findings from an integrative literature review on the current state of rural health needs for adolescents. Adolescence is typically considered to occur between the ages of 13 and 19 years (American Academy of Child and Adolescent Psychiatry, 2008). During these years, adolescents become more independent and autonomous and often make decisions with lifetime implications for their health. Many of the health related issues experienced by adolescents are preventable and are often related to risky behavior by adolescents (Shannon & Broussard, 2011). Risky behaviors such as substance use and abuse, smoking, and unprotected sex have been targeted as leading health indicators for adolescent health in the Healthy People 2020 initiative (HHS, Healthy People 2020, 2011). Adolescents living in rural areas may be at greater risk for poor health outcomes than their urban and suburban counterparts (Curtis, Waters, & Brindis, 2011). An integrative review was undertaken to determine the most common health concerns of rural dwelling adolescents as a path to develop evidence-based curriculum and interventions that are likely to promote health in rural youth at risk.

We study numerically and analytically first- and second-order phase transitions in neuronal networks stimulated by shot noise (a flow of random spikes bombarding neurons). Using an exactly solvable cortical model of neuronal networks on classical random networks, we find critical phenomena accompanying the transitions and their dependence on the shot noise intensity. We show that a pattern of spontaneous neuronal activity near a critical point of a phase transition is a characteristic property that can be used to identify the bifurcation mechanism of the transition. We demonstrate that bursts and avalanches are precursors of a first-order phase transition, paroxysmal-like spikes of activity precede a second-order phase transition caused by a saddle-node bifurcation, while irregular spindle oscillations represent spontaneous activity near a second-order phase transition caused by a supercritical Hopf bifurcation. Our most interesting result is the observation of the paroxysmal-like spikes. We show that a paroxysmal-like spike is a single nonlinear event that appears instantly from a low background activity with a rapid onset, reaches a large amplitude, and ends up with an abrupt return to lower activity. These spikes are similar to single paroxysmal spikes and sharp waves observed in EEG measurements. Our analysis shows that above the saddle-node bifurcation, sustained network oscillations appear with a large amplitude but a small frequency in contrast to network oscillations near the Hopf bifurcation that have a small amplitude but a large frequency. We discuss an amazing similarity between excitability of the cortical model stimulated by shot noise and excitability of the Morris-Lecar neuron stimulated by an applied current., Comment: 15 pages, 9 figures. arXiv admin note: substantial text overlap with arXiv:1304.3237