Mast cells are key effector cells in the early phase allergic inflammation and in diverse immunological and pathological processes. In order to understand the effect on reduction of the ...anti-dinitrophenyl (DNP) IgE antibody-induced b-hexosaminidase release in RBL-2H3 rat mast cells, a novel series of 4-senecioyloxy- methyl-6,7-dimethoxycoumarins (SMDC) was prepared by reacting 4-chloromethyl-6,7-dimethoxycoumarin with various carboxylic acids. Compounds 8-11 with cyclic moiety such as phenyl, thiophenyl, pyridinyl, and furanyl group were found to inhibit-hexosaminidase release more potently (5.98-9.62 mM) than compounds 3-7 and 12 with acyclic moiety (19.32-76.78 mM). Furthermore, compounds 8 and 9 inhibited IgE-induced ear swelling and significantly reduced systemic passive cutaneous anaphylaxis reaction in mice. KCI Citation Count: 1
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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.
We evaluated the survival benefits of primary tumor removal in stage IV breast cancer patients. The median survival of patients who had undergone surgery was longer than that of patients who had ...received systemic therapy only (118 vs. 28 months). On multivariate analysis, fewer distant metastases, surgery of the primary tumor, a better response to chemotherapy, and luminal A subtype were significant predictors for better survival.
Several studies have suggested that primary tumor removal improved overall survival for patients with stage IV breast cancer. However, the survival benefit of local treatment remains controversial. The purpose of the present study was to determine whether surgical removal of the primary tumor provides survival benefits to patients with stage IV breast cancer.
We retrospectively reviewed the medical records of 155 patients with an initial diagnosis of stage IV breast cancer at Seoul National University Bundang Hospital from 2003 to 2014. Kaplan-Meier analysis was used to estimate the median survival. The log-rank test was used to compare differences in patient and tumor characteristics. Multivariate Cox regression analysis for survival was used, controlling for potential confounding variables.
Of 155 patients with stage IV breast cancer, 95 (61%) underwent surgical removal of the primary tumor. The median follow-up period was 59 months (95% confidence interval CI, 45-73 months). The median survival was longer for the patients with a better response to chemotherapy (70 vs. 47 months; P = .010) and for those who had undergone surgery (118 vs. 28 months; P < .001) than for those who without a better chemotherapy response or surgery. The median survival of the patients who received radiotherapy was better than that of the patients who did not (65 vs. 39 months; P = .004). Patients with luminal A cancer had a median survival of 118 months, the longest compared with those with other subtypes (P = .001). In addition, patients with distant metastasis at a single site had a longer median survival than did those with multiple metastatic sites. The multivariate Cox regression analysis revealed that fewer distant metastases, surgery of the primary tumor, a better response to chemotherapy, and luminal A subtype were significant independent predictors of survival.
Our results showed that primary tumor removal was independently associated with improvement in survival. Therefore, surgical management for the primary tumor could be considered more actively in patients with stage IV breast cancer.
Epstein-Barr virus (EBV) is involved in the pathogenesis of angioimmunoblastic T-cell lymphoma (AILT), but its precise role and prognostic impact are not clear. This study aimed to evaluate the ...incidence of EBV-postitivity in the tumor and bone marrow (BM) samples from AILT patients, and their correlations with the clinical variables and patient survival.
Seventy AILT cases were identified over a period of 8 years. Twenty seven cases were investigated for their EBV tumor status, and 10 BM samples of these patients were investigated for their EBV status with using in situ hybridization (ISH). EBV PCR was performed for the BM mononuclear cells in 8 cases.
Among the 27 tumor specimens, ten (37%) were EBV-positive. Only CD20-negativity in tumor correlated with the EBV-positivity (p = 0.035). In 13 (48%) patients, gross tumor involvement was recognized by hematoxylin-eosin staining at the time of diagnosis. Among the 10 patients who had additional BM slides available, there were 3 with BM involvement, and none showed EBV positive results on ISH. EBV PCR of the BM mononuclear cells revealed one-positive case among 8 patients. This patient was negative for both BM involvement and EBV ISH. The median overall survival of the 25 treated patients was 48.9 months (95% CI: 18.6 approximately 79.2 months). Neither overall survival nor progression-free survival was related with EBV-positivity of the tumor.
EBV-positivity of tumor had no impact on the prognosis of AILT patients.
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Background: Participation in clinical trials gives patients with cancer a chance to receive potential benefits, such as experimental treatment, meticulous follow-up and toxicity ...managements. We aimed to assess the evidence that such an effect exists in patients with gastric cancer. Methods: Clinical characteristics and overall survival of patients with metastatic or recurrent gastric cancer who received fluoropyrimidine and platinum combination palliative chemotherapy within or outside clinical trials at tertiary referral hospital from January 2010 to December 2012 were retrospectively analyzed. Results: Of the 244 patients, 84 patients (34%) were enrolled in clinical trials. During the study period, 20 patients in four phase 3 trials, 54 patients in eight phase 2 trials and ten patients in two phase 1 trials were participated in clinical trials. Twenty patients (8%) at first-line and 64 patients (38%) at second-line or later were enrolled in clinical trials. Younger age (P = 0.014), metastatic disease (P = 0.015) and HER2 IHC status (P = 0.005) were correlated with participation in clinical trials. The median overall survival of patients who participated in clinical trials at first-line was better than those who did not participated in clinical trials, although it was not statistically significant (16 months and 11 months, respectively, P = 0.407). Number of participation in clinical trials was not associated with survival outcome (1 versus ≥ 2 trials: 15 months and 18 months, respectively, P = 0.545). Second-line chemotherapy was administered in 167 patients. The median overall survival of patients who participated in clinical trials at second-line or later was also better than those who did not participated in clinical trials, however, it was not statistically significant (9 months and 6 months, respectively, P = 0.101). Conclusions: Younger patients, metastatic disease, positive HER2 IHC status, and clinical setting of second-line or later were associated with more participation in clinical trials. The median overall survival was numerically longer in patients who were enrolled in the clinical trials although it was not statistically significant.
Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. ...This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44+/CD24− and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal–HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal–HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44+/CD24− and ALDH1+ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44+/CD24-cell (+) tumors than in CD44+/CD24-cell (−) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (−) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.
The purposes of this study were to determine whether Cervi Pantotrichum Cornu (CPC) has osteogenic activities in human osteoblastic MG-63 cells and to investigate the underlying molecular mechanism.
...The effects of CPC on alkaline phosphatase activity, collagen synthesis, and calcium deposits were measured. The COL1A1, ALPL, BGLAP, and SPP1 expressions were measured by real-time PCR. Phosphorylated MAP kinases (ERK1/2, JNK1/2, p38, ELK1, and cJUN) were studied by western blot analysis. The involvement of MAPK pathway in osteogenic gene expressions was determined by using each selective MAPK inhibitor (PD98059, SP600125, and SB203580).
CPC increased alkaline phosphatase activity, collagen synthesis, and calcium deposits. CPC activated ERK1/2, JNK1/2, p38, and ELK1 phosphorylation except cJUN. CPC increased the COL1A1, ALPL, BGLAP, and SPP1 gene expressions. The elevated COL1A1 and BGLAP expressions were inhibited by PD98059, SP600125 or SB203580. The elevated ALPL expression was blocked by SB203580. The elevated SPP1 expression was inhibited by SP600125 or SB203580. CPC increased COL1A1 and BGLAP expressions via ERK1/2, JNK1/2, and p38 MAPKs pathways and SPP1 expression via JNK1/2 and p38 pathways. p38 pathway is needed for ALPL expression.
These results imply that MAPK signaling pathway is an indispensable factor for bone matrix genes expression of CPC in MG-63 human osteoblast-like cells.
We proposed and tested a method to estimate sleep period time (SPT) using electrodermal activity (EDA) signals. Eight healthy subjects and six obstructive sleep apnea patients participated in the ...experiments. Each subject's EDA signals were measured at the middle and ring fingers of the dominant hand during polysomnography (PSG). For nine of the 17 participants, wrist actigraphy was also measured for a quantitative comparison of EDA- and actigraphy-based methods. Based on the training data, we observed that sleep onset was accompanied by a gradual reduction of amplitude of the EDA signals, whereas sleep offset was accompanied by a rapid increase in amplitude of EDA signals. We developed a method based on these EDA fluctuations during sleep-wake transitions, and applied it to a test dataset. The performance of the method was assessed by comparing its results with those from a physician's sleep stage scores. The mean absolute errors in the obtained values for sleep onset, offset, and period time between the proposed method, and the results of the PSG were 4.1, 3.0, and 6.1 min, respectively. Furthermore, there were no significant differences in the corresponding values between the methods. We compared these results with those obtained by applying actigraphic methods, and found that our algorithm outperformed these in terms of each estimated parameter of interest in SPT estimation. Long awakening periods were also detected based on sympathetic responses reflected in the EDA signals. The proposed method can be applied to a daily sleep monitoring system.
Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse ...large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4-29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.
Umbilical cord blood (UCB) has recently been recognized as a new source of mesenchymal stem cells (MSCs) for use in stem cell therapy. We studied the effects of systemic injection of human UCB-MSCs ...and their conditioned medium (CM) on ovariectomy (OVX)-induced bone loss in nude mice. Ten-week-old female nude mice were divided into six groups: Sham-operated mice treated with vehicle (Sham-Vehicle), OVX mice subjected to UCB-MSCs (OVX-MSC), or human dermal fibroblast (OVX-DFB) transplantation, OVX mice treated with UCB-MSC CM (OVX-CM), zoledronate (OVX-Zol), or vehicle (OVX-Vehicle). Although the OVX-Vehicle group exhibited significantly less bone mineral density (BMD) gain compared with the Sham-Vehicle group, transplantation of hUCB-MSCs (OVX-MSC group) has effectively prevented OVX-induced bone mass attenuation. Notably, the OVX-CM group also showed BMD preservation comparable to the OVX-MSC group. In addition, microcomputed tomography analysis demonstrated improved trabecular parameters in both the OVX-MSC and OVX-CM groups compared to the OVX-Vehicle or OVX-DFB group. Histomorphometric analysis showed increased bone formation parameters, accompanied by increased serum procollagen type-I N-telopeptide levels in OVX-MSC and OVX-CM mice. However, cell-trafficking analysis failed to demonstrate engraftment of MSCs in bone tissue 48 h after cell infusion. In vitro, hUCB-MSC CM increased alkaline phosphatase (ALP) activity in human bone marrow-derived MSCs and mRNA expression of collagen type 1, Runx2, osterix, and ALP in C3H10T1/2 cells. Furthermore, hUCB-MSC CM significantly increased survival of osteocyte-like MLO-Y4 cells, while it inhibited osteoclastic differentiation. To summarize, transplantation of hUCB-MSCs could effectively prevent OVX-mediated bone loss in nude mice, which appears to be mediated by a paracrine mechanism rather than direct engraftment of the MSCs.
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