In Suh Park

Multifunctional doxorubicin loaded superparamagnetic iron oxide nanoparticles for chemotherapy and magnetic resonance imaging in liver cancer

To develop a drug delivery system with enhanced efficacy and minimized adverse effects, we synthesized a novel polymeric nanoparticles, (YCC-DOX) composed of poly (ethylene oxide)-trimellitic anhydride chloride-folate (PEO-TMA-FA), doxorubicin (DOX) and superparamagnetic iron oxide (Fe(3)O(4)) and folate. The efficacy of the nanoparticles was evaluated in rats and rabbits with liver cancer, in comparison with free-DOX (FD) and a commercial liposome drug, DOXIL. YCC-DOX showed the anticancer efficacy and specifically targeted folate receptor (FR)-expressing tumors, thereby increasing the bioavailability and efficacy of DOX. The relative tumor volume of the YCC-DOX group was decreased two- and four-fold compared with the FD and DOXIL groups in the rat and rabbit models, respectively. Furthermore, YCC-DOX showed higher MRI sensitivity comparable to a conventional MRI contrast agent (Resovist), even in its lower iron content. In the immunohistochemical analysis, YCC-DOX group showed the lower expression of CD34 and Ki-67, markers of angiogenesis and cell proliferation, respectively, while apoptotic cells were significantly rich in the YCC-DOX group in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. These results indicate that YCC-DOX is a promising candidate for treating liver cancer and monitoring the progress of the cancer using MRI.

Prevention of Metastasis in a 4T1 Murine Breast Cancer Model by Doxorubicin Carried by Folate Conjugated pH Sensitive Polymeric Micelles

This study primarily focused on the anti-metastatic activity of doxorubicin (DOX) loaded in a pH-sensitive mixed polymeric micelle formed from two block polymers: poly(L-lactide) (PLLA) (Mn 3000)-b-poly(ethylene glycol) (PEG) (Mn 2000)-folate and poly(L-histidine) (PHis) (Mn 4700)-b-PEG (Mn 2000). Tumor formation and metastasis in mice were examined using a murine mammary carcinoma cell of 4T1 which is one of the most aggressive metastatic cancer cell lines. The efficacy was evaluated by tumor size, body weight change, survival rate, dorsal skin fold window chamber model, and histological observation of the lung, heart, liver and spleen after treatment with various DOX formulations. When the tumor reached 50-100 mm³ in size, the mice were treated 4 times at a 3-day interval at a dose of 10 mg DOX/kg. The mixed micelle formulation resulted in retarded tumor growth, no weight loss, and no death for 4-5 weeks. In another set of the in vivo test for histological evaluation of the organs, the mice were similarly treated but the formulations were injected one day after 4T1 cell inoculation. The treatment by DOX loaded mixed micelle showed no apparent metastasis till 28 days. However, significant metastasis to the lung and heart was observed on Day 28 when the mice were treated with DOX carried by PBS, PLLA-b-PEG micelle and PHis-b-PEG micelle.

Quality of life in Korean patients with inflammatory bowel diseases : ulcerative colitis, Crohn's disease and intestinal Behçet's disease

Abstract Health-related quality of life (HRQOL) is an important outcome factor in chronic diseases such as inflammatory bowel disease (IBD). This study used the Korean translation of the disease-specific, self-administered Inflammatory Bowel Disease Questionnaire (IBDQ) to compare HRQOL in ulcerative colitis (UC; n=98), Crohns disease (CD; n = 49), and intestinal Behçets disease (BD; n = 34). In addition to the current status, patients were asked retrospectively to recall their symptoms at the beginning and during the worst period of their disease. Disease activity was measured by St. Marks Activity Index, Crohns disease Activity Index (CDAI), and the Harvey-Bradshaw Index (HBI). In all IBD patients, including those with BD, the IBDQ total score during the worst period was significantly lower than that at present and that at the beginning of the disease. However, there were no significant differences between groups regarding the total IBDQ score or its various dimensions. In UC a strong correlation between IBDQ scores and St. Marks Activity Index was observed (r = –0.708, P<0.001). IBDQ scores were also highly correlated with CDAI and HBI in both CD (r=–0.506, P<0.001 for CDAI; r = –0.600, P<0.001 for HBI) and BD (r = –0.687, P<0.001 for CDAI; r = –0.531, P<0.001 for HBI). However, the current IBDQ score was not related to demographic parameters such as gender, age, educational status, economic status, and marital status as well as disease factors such as duration of disease, history of operation or hospital admission, extent of disease in UC, involved region in CD, and clinical type in BD. We conclude that the Korean IBDQ is a responsive and promising instrument for measuring HRQOL of IBD patients in clinical trials. In addition, the IBDQ can be helpful in developing a disease-specific activity index in BD.

Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach

Cisplatin has been one of the most widely used anticancer agents, but its nephrotoxicity remains a dose-limiting complication. Here, we evaluated the idiopathic nature and the predose prediction of cisplatin-induced nephrotoxicity using a nuclear magnetic resonance (NMR)-based pharmacometabonomic approach. Cisplatin produced serious toxic responses in some animals (toxic group), but had little effect in others (nontoxic group), as judged by hematological and histological results. The individual metabolic profiles, assessed by urine NMR spectra, showed large differences between the post-administration profiles of the two groups, indicating the relevance of the NMR approach. Importantly, multivariate analysis of the NMR data showed that the toxic and nontoxic groups can be differentiated based on the pretreatment metabolite profiles. Leave-one-out analysis, performed to evaluate the practical performance of our approach, gave a 66% accuracy rate in predicting toxic responses based on the pretreatment metabolite profiles. Hence, we provide a working model that can explain the idiopathic toxicity mechanism based on marker metabolites found by NMR analysis consistent with tissue NADH measurements. Thus, a pharmacometabonomic approach using pretreatment metabolite profiles may help expedite personalized chemotherapy of anticancer drugs.

Effects of Nonsteroidal Anti-Inflammatory Drugs on Helicobacter pylori-Infected Gastric Mucosae of Mice: Apoptosis, Cell Proliferation, and Inflammatory Activity

ABSTRACT Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are two well-known important causative factors of gastric damage. While H. pylori increases apoptosis and the proliferation of gastric epithelial cells and is an important factor in peptic ulcer and gastric cancer, NSAIDs induce cell apoptosis and have antineoplastic effects. We investigated the effects of NSAIDs (a nonselective cyclooxygenase [COX] inhibitor [indomethacin] and a selective COX-2 inhibitor [NS-398]) on the apoptosis and proliferation of gastric epithelial cells and gastric inflammation inH. pylori-infected mice. C57BL/6 mice were sacrificed 8 weeks after H. pylori SS1 inoculation. Indomethacin (2 mg/kg) or NS-398 (10 mg/kg) was administered subcutaneously once daily for 10 days before sacrifice. The following were assessed: gastric inflammatory activity, gastric COX protein expression by Western blotting; gastric prostaglandin E2 levels by enzyme immunoassay, apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and cell proliferation by Ki67 immunostaining. Compared to the controls, H. pylori infection and/or NSAID treatment increased COX-1 and COX-2 protein expression. Gastric prostaglandin E2 levels, apoptotic index, cell proliferation index, neutrophil activity, and the degree of chronic inflammation were all increased by H. pylori infection, and these effects were significantly decreased by indomethacin treatment. However, NS-398 treatment after H. pylori infection did not induce a significant reduction, although it did result in a tendency to decrease. These results show that NSAIDs can reverse the increased apoptosis and proliferation of epithelial cells and inflammatory activity in the stomachs of H. pylori-infected mice and that, like COX-2 activation, COX-1 induction contributes to the change of gastric mucosal cell turnover and inflammation induced by H. pylori infection.

Comparison of immunomodulative effects of the histamine-2 receptor antagonists cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells in gastric cancer patients

BACKGROUND Histamine-2 receptor antagonist (H2-RA) have been shown to improve the function of various parts of the immune system. The proposed mechanism of the immunomodulative effects of H2-RA has been considered to be the inhibition of suppressor T-lymphocyte activity, an increase in interleukin-2 production, and an enhancement of natural killer cell activity. Most of these studies were done with cimetidine. Comparative data with other H2-RA are limited and conflict on immunomodulative effects. Comparison of the actions of H2-RA on the immune system is required. METHODS We compared the immunodulative effect of the H2-RAs cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells (PBMC) in normal controls and patients with gastric cancer. DNA synthesis, cytotoxicity against K562 cells, and the levels of soluble interleukin-2 receptor (sIL-2R) in supernatant were measured after addition of the various H2-RA to PBMC cultures. RESULTS Subjects with gastric cancer showed significantly higher levels of suppressor lymphocyte activity than normal controls. These levels were restored to levels of normal controls by the addition of cimetidine. Statistically significant lymphoblastogenesis and cytotoxicity against K562 cells were observed only in cimetidine-treated PBMC (p < 0.05); such effects were not observed in ranitidine- or famotidine-treated PBMC. Significantly increased levels of sIL-2R were found in supernatants obtained from culture flasks treated with cimetidine and phytohemagglutinin or ranitidine and phytohemagglutinin (p < 0.01). CONCLUSIONS Of the three H2-RAs tested, cimetidine had the strongest and famotidine the weakest immunomodulating effect. Only cimetidine augmented the cytotoxicity and proliferative response of lymphocyte to mitogen; neither ranitidine nor famotidine had such an effect. These results might be due to their structural differences. In addition, the immunologic effects of H2-RA are unlikely to be mediated via specific interaction at the H2 receptor.

Analysis of age-related changes in the functional morphologies of salivary glands in mice

BACKGROUND AND OBJECTIVES Salivary glands in the elderly commonly exhibit salivary dysfunction resulting dry mouth, poor oral hygiene, and dental caries. However, in vivo changes of salivary glands during aging have not been well documented in the literature. This study was undertaken to determine age-related morphometric and functional changes of salivary glands using an aging mouse model. METHODS Male C57BL/6 mice were divided into three groups, group A (10 weeks old; n=10), group B (30 weeks old; n=10), and group C (90 weeks old; n=10). Body weights, salivary gland weights, salivary flow rates, and salivary lag times were measured and compared. Histomorphometric examinations and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed. In addition, changes in salivary uptake and excretion were observed by single-photon emission computed tomography (SPECT). RESULTS Body and gland weights increased with age. Gland weight was significantly higher in group B than in groups A and C. Salivary lag time was significantly greater in group C than in groups A and B, and salivary flow rate was significantly greater in group B than in groups A and C. Histologic evaluations exhibited acinar cell atrophy, cytoplasmic vacuolization, lymphocyte infiltration, small mucin component and more periductal fibrosis in salivary glands of group C. TUNEL assays revealed that apoptotic salivary epithelial cells were significantly more numerous in group C than in groups A and B. (99m)Tc-pertechnetate excretion rate was significantly lower in group C than in groups A and B in SPECT. CONCLUSION Various morphometric and histopathological changes were observed in the salivary glands of aging mouse as well as relevant functional alterations, such as, decreased saliva production and excretion. Increased number of apoptotic salivary epithelial cells may contribute to the observed functional deterioration.

Reclassifying Formerly Indeterminate Thyroid FNAs Using the Bethesda System Reduces the Number of Inconclusive Cases

Objective: To evaluate the effectiveness of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) and to analyze the causes of unclear diagnoses following BSRTC adoption. Study Design: According to the BSRTC, we reclassified cytologic samples originally diagnosed as ‘indeterminate’ with sequential surgical resection. Then, we analyzed the causes of cases, which were recategorized as ‘atypia undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)’. Results: According to the BSRTC, 154 ‘indeterminate’ cases were reclassified as follows: unsatisfactory, n = 5 (3.2%); benign, n = 43 (27.9%); AUS/FLUS, n = 77 (50.0%); suspicious for a follicular neoplasm, n = 7 (7.1%); suspicious for a Hürthle cell neoplasm, n = 4 (2.6%); suspicious for malignancy, n = 15 (9.7%), and malignancy, n = 3 (1.9%). Then, the AUS/FLUS group was analyzed according to the scenarios proposed by the BSRTC. Fifty-nine (58.9%) cases of AUS/FLUS were due to suboptimal preparation. In addition, papillary microcarcinoma and coexisting Hashimoto’s thyroiditis caused inconclusive diagnoses. Conclusion: The BSRTC can be easily applied to thyroid fine-needle aspiration. We were able to reclassify indeterminate thyroid nodules into more detailed categories and thus reduce the number of cases classified as indeterminate. However, suboptimal preparation, papillary microcarcinoma, and coexisting Hashimoto’s thyroiditis precluded cytopathologists from making definitive diagnoses.

Adjuvant treatment of operable stomach cancer with polyadenylic·polyuridylic acid in addition to chemotherapeutic agents: A preliminary report

A randomized trial of polyadenylic.polyuridylic acid [poly(A).poly(U)] in addition to chemotherapy was undertaken in patients with stomach cancer following curative gastrectomy. They were randomized into a group of 108 patients receiving chemotherapy plus poly(A).poly(U) and a control group of 116 patients receiving chemotherapy alone. Chemotherapy consisted of injections of 5-fluorouracil, 12 mg/kg once weekly and adriamycin, 40 mg/m2 once every 3 weeks, continuously after operation. Poly(A).poly(U) was infused in a 100 mg dose, once a week six times from 5 days after the first injection of chemotherapeutic agents and 6 months later in a half dose similarly. At 55 months after initiation of the trial, the mean follow-up periods were 24 months for both groups. It has been revealed that patients who received the combined treatment postoperatively showed a lesser mortality and lower rate of recurrence, both reflecting significant increases in overall (P less than 0.05) and relapse-free (P less than 0.02) survivals as compared to those who received chemotherapy alone. This effect is more pronounced in patients having moderately advanced lymphnode involvement (N1) than in patients without (N0) or more advanced (N2) involvement. Thus, poly(A).poly(U) appears to be an effective agent when used postoperatively with chemotherapy in stomach cancers.

Endometrial stromal sarcoma of the small bowel: a case report and review of literature

Endometrial stromal sarcoma (ESS) is a rare mesenchymal neoplasm of the uterus, which is predominantly composed of endometrial stromal cells. When this feature is encountered in the extragenital area, the diagnosis is sometimes difficult especially if endometriosis is not present. We report a case of ESS arising in the small bowel without associated endometriosis in a 75-year-old woman and review the literatures for 16 cases of extrauterine extraovarian ESS. The most common site of the extrauterine extraovarian ESS is the gastrointestinal tract (8/16 cases). It is intimately associated with endometriosis (12/16 cases) as the case of ovarian ESS. Most ESSs were immunoreactive for CD10 (5/5 cases), progesterone receptor (10/10 cases), and estrogen receptor (9/11 cases), and negative for CD34 (0/7 cases). It may have a higher tendency for dissemination beyond its site of origin (12/16 cases) than its uterine counterpart. In conclusion, a careful morphological examination combined with immunohistochemical studies and consideration of ESS in the differential diagnosis would help in obtaining an accurate diagnosis in these rare circumstances.