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To evaluate the curative effect of one-stage posterior debridement and osteotomy parallel to the endplates for reconstruction, deformity correction, and tuberculosis control on treating the spinal tuberculosis of graded GATA III. From July of 2012 to December of 2017, there were 36 cases from the Second Hospital of Shanxi Medical University with thoracic and lumbar tuberculosis graded GATA III, in which we used osteotomy parallel to the endplates and reconstruction for treatment,16 for males and 20 for females. The local Cobb angles of kyphosis of all patients are greater than or equal to 20.The age varied from 28 months to 72 years with an average of 38.8 years. There were 15 cases of thoracic segment, 12 cases of thoracolumbar segment (T11 -L2 ), 9 cases of lumbar segment. Preoperative results of ASIA were 3 cases of grade C,5 cases of grade D and 28 cases of grade E with an average kyphosis Cobb angle of 37.21 ± 3.28. The visual analogue scale(VAS) scores preoperatively were 0-8 points (averaged 5.58 ± 1.66 points). All the patients had paraspinal abscesses. After completing the preoperative examinations and evaluations, the osteotomy parallel to the endplates and reconstruction were executed. We made a statistical analysis of the Cobb angles, visual analogue scale(VAS) scores, erythrocyte sedimentation rate (ESR), C-reaction protein(CRP), and ASIA grades before and after the surgery. The following-up time varied from 12 to 24 months, with an average of 18 months. The VAS score improved from 5.58 ± 1.66 before the surgery to 3.25 ± 0.92 one month after the surgery and 2.12 ± 0.73 at the last follow-up. The Cobb angles decreased from 37.21° ± 3.28° before the surgery to 5.72°± 2.66° one month later and 5.99° ± 1.92° at the last follow-up. The ESR decreased from 55.34 ± 1.72 mm/1 h before the surgery to 28.22 ± 3.76 mm/1 h one month later and 11.54 ± 0.46 mm/1 h at the last follow-up. The CRP decreased from 35.22 ± 2.46 mg/L before to 12.67 ± 2.82 mg/L and 4.50 ± 2.11 mg/L at the last follow-up. The results of the last ASIA grades were 1 case of grade D and 35 cases of grade E. The one-stage posterior debridement and osteotomy parallel to the endplates for patients with spinal tuberculosis of graded GATA III are not only beneficial to spinal reconstruction, but also obtain ideal reconstuction effects. more...

The efficacy of gold nanoparticle (AuNP)-assisted radiofrequency (RF)-induced hyperthermia employing the Kanzius device remains controversial. Different from the Kanzius device, modulated electro-hyperthermia (mEHT) utilizes the capacitive-impedance coupled 13.56 MHz radiofrequency (RF) current and has been approved for clinical cancer treatment. In this study, we investigated the heating characteristics of spherical-, urchin-, and rod-like AuNPs of a similar 50 nm size upon exposure to a 13.56 MHz radiofrequency using the LabEHY-105CL, an more...

Helicobacter pylori (H. pylori) is one of the most important pathogenic bacteria associated with various gastrointestinal diseases. At present, its apoptotic or antiapoptotic mechanism on gastric epithelial cells remains unknown and needs further illustrated. In this study, acute infection model (H. pylori and GES-1 cells were co-cultured for 24 h at a multiplicity of infection MOI of 100:1) and chronic infection model (GES-1 cells were infected repeatedly every 24 h at a multiplicity of infection MOI of 100:1 for approximately 8 weeks) were established, respectively. the chronic H. pylori infected GES-1 cells underwent a typically morphological change and Western Blot results showed that there was slight decrease in expression of E-cadherin, and obvious increase in expression of Vimentin. Apoptosis of these two models were analyzed by flow cytometry compared with the control cells, meanwhile, apoptosis associated markers (Bcl-xL, Bcl-2, Bax, etc) were detected by Western blot, additional in clinical H. pylori-positive gastric cancer tissues. Results showed that compared with the control cells, acute infection of H. pylori significantly accelerated the apoptosis of GES-1, increased the expression of Bax and Cleaved caspase-3, down-regulated expression of Bcl-xL and Bcl-2. Moreover, an opposite result was found in chronic infection of model and clinical gastric cancer tissues, and enhanced expression of NF–κB p65. Taken together, these findings suggest that H. pylori infection plays differential effects on apoptosis of gastric epithelial cells. more...

Modulated electro-hyperthermia (mEHT) is a form of mild hyperthermia (HT) used for cancer treatment. The principle utility of HT is the ability not only to increase cell temperature, but also to increase blood flow and associated pO2 to the microenvironment. While investigational evidence has shown the unique ability of mEHT to elicit apoptosis in cancer cells, in vivo and in vitro, the same trait has not been observed with conventional HT. There is dissension as to what allows mEHT to elicit apoptosis despite heating to only mild temperatures, with the predominant opinion in favor of increased temperature at a cellular level as the driving force. For this study, we hypothesized that in addition to temperature, the amount of electrical energy delivered is a major factor in induction of apoptosis by mEHT. To evaluate the impact of electrical energy on apoptosis, we divided generally practiced mEHT treatment into 3 phases: Phase I (treatment start to 10 min. mark): escalation from 25 °C to 37 °C Phase II (10 min. mark to 15 min. mark): escalation from 37 °C to 42 °C Phase III (15 min. mark to 45 min. mark): maintenance at 42 °C Combinations of mEHT at 18 W power, mEHT at 7.5 W power, water bath, and incubator were applied to each of the three phases. Power output was recorded per second and calculated as average power per second. Total number of corresponding Joules emitted per each experiment was also recorded. The biological effect of apoptotic cell death was assayed by annexin-V assay. In group where mEHT was applied for all three phases, apoptosis rate was measured at 31.18 ± 1.47%. In group where mEHT was only applied in Phases II and III, apoptosis rate dropped to 20.2 ± 2.1%. Where mEHT was only applied in Phase III, apoptosis was 6.4 ± 1.7%. Interestingly, when mEHT was applied in Phases I and II, whether Phase III was conducted in either water bath at 42 °C or incubator at 37 °C, resulted in nearly identical apoptosis rates, 26 ± 4.4% and 25.9 ± 3.1%, respectively. These results showed that accumulation of mEHT at high-powered setting (18 W/sec) during temperature escalation (Phase I and Phase II), significantly increased apoptosis of tested cancer cells. The data also showed that whereas apoptosis rate was significantly increased during temperature escalation by higher power (18 W/sec), apoptosis was limited during temperature maintenance with lower power (7.5 W/sec). This presents that neither maintenance of 42 °C nor accumulation of Joules by mEHT has immediate correlating effect on apoptosis rate. These findings may offer a basis for direction of clinical application of mEHT treatment. more...

Background The aim of this study was to use the liquid chromatography/tandem mass spectrometry (LC‐MS/MS) method to quantitate levels of three urinary glycosaminoglycans (GAGs; dermatan sulfate [DS], heparan sulfate [HS], and keratan sulfate [KS]) to help make a correct diagnosis of mucopolysaccharidosis (MPS). Methods We analyzed the relationships between phenotypes and levels of urinary GAGs of 79 patients with different types of MPS. Results The patients with mental retardation (n = 21) had significantly higher levels of HS than those without mental retardation (n = 58; 328.8 vs. 3.2 μg/ml, p more...

Objective: Stroke is the leading cause of death and disability, and is closely related to a lack of exercise. Currently, most Chinese medical staff members lack exercise and may be at risk for stroke. We sought to determine the risk factors for stroke and study the significance of health-related physical fitness testing in stroke prevention among Chinese medical staff members. Methods: A total of 627 subjects from Urumqi, Xinjiang, China, were included in the study and a survey was conducted from 1st January 2016 to 1st February 2016. Stroke screening and health-related physical fitness testing were completed according to the standard protocol, and the related data were analyzed. Results: Based on the screening, 27.6% (n = 173) of the subjects were at high risk for stroke. The top risk factors for stroke in these subjects were dyslipidemia, lack of exercise or mild physical activity, being overweight or obese, and high blood pressure. Body weight, body mass index, body fat, visceral fat area, body fat percentage, and basal metabolic rate were significantly higher (P more...

Purpose: True abscopal responses from radiation therapy are extremely rare; the combination of immune checkpoint inhibitors with radiation therapy has led to more reports of the abscopal effect, but even in this setting, the genuine magnitude remains unknown and is still considered generally uncommon. We report the occurrence of what appears to be putative, durable abscopal tumor responses with associated auto-immune systemic reactions resulting from the combination of local radiotherapy (RT) and modulated electrohyperthermia (mEHT). Materials and Methods: Data from advanced cancer patients treated palliatively with RT and mEHT between January and December 2017 were collected as part of a post-marketing safety monitoring program of mEHT therapy. We specified a minimum RT dose of 30 Gy and at least four mEHT treatments for reporting toxicities, which was the primary aim of the larger study. Results: Thirty-three patients treated with RT and mEHT, both applied to the same lesion, were included. The median RT dose was 45.5 Gy in 20 fractions (fxs) and the median number of mEHT treatments was 12 (range, 4–20). Most patients had subsequent systemic therapy after one course of RT and mEHT. Three patients (9.1%) developed autoimmune toxicities. Case number 1 received RT and mEHT only; case number 2 had two cycles of concurrent low dose chemotherapy during RT; and case number 3 received concurrent immune checkpoint inhibitors. None of the three patients received any further systemic treatment due to obvious treatment-related autoimmune reactions which occurred rapidly after RT; one had autoimmune hepatitis, one had dermatitis herpetiformis and the third developed severe myasthenia gravis. Interestingly, what we surmise to be long-lasting abscopal responses outside the irradiated area, were noted in all three patients. Conclusion: RT combined with mEHT could putatively result in enhancing immune responsiveness. These preliminary observational findings lead to the generation of a hypothesis that this combination induces both an in-situ, tumor-specific immune reaction and an anti-self-autoimmune reaction, in at least a small proportion of patients, and of those who experience the auto-immune response, tumor response is a concomitant finding. Mechanisms underlying this phenomenon need to be investigated further. more...

// Kai-Lin Yang 1, 2, 3 , Cheng-Chung Huang 1 , Mau-Shin Chi 1 , Hsin-Chien Chiang 1 , Yu-Shan Wang 1 , Chien-Chung Hsia 4 , Gabor Andocs 5 , Hsin-Ell Wang 2 , Kwan-Hwa Chi 1, 2, 6 1 Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 2 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 3 School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan 4 Institute of Nuclear Energy Research, Taoyuan, Taiwan 5 Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan 6 Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan Correspondence to: Kwan-Hwa Chi, email: M006565@ms.skh.org.tw Hsin-Ell Wang, email: hewang@ym.edu.tw Keywords: modulated electro-hyperthermia, conventional capacitive coupling hyperthermia, water bath, cytotoxicity, cell membrane Received: May 03, 2016 Accepted: August 11, 2016 Published: August 20, 2016 ABSTRACT Radiofrequency-induced hyperthermia (HT) treatments for cancer include conventional capacitive coupling hyperthermia (cCHT) and modulated electro-hyperthermia (mEHT). In this study, we directly compared these methods with regard to in vitro cytotoxicity and mechanisms of action under isothermal conditions. Hepatoma (HepG2) cells were exposed to HT treatment (42°C for 30 min) using mEHT, cCHT or a water bath. mEHT produced a much higher apoptosis rate (43.1% ± 5.8%) than cCHT (10.0% ± 0.6%), the water bath (8.4% ± 1.7%) or a 37°C control (6.6% ± 1.1%). The apoptosis-inducing effect of mEHT at 42°C was similar to that achieved with a water bath at 46°C. mEHT also increased expression of caspase-3, 8 and 9. All three hyperthermia methods increased intracellular heat shock protein 70 (Hsp70) levels, but only mEHT greatly increased the release of Hsp70 from cells. Calreticulin and E-cadherin levels in the cell membrane also increased after mEHT treatment, but not after cCHT or water bath. These results suggest that mEHT selectively deposits energy on the cell membrane and may be a useful treatment modality that targets cancer cell membranes. more...

Background Tumor cells continuously evolve over time in response to host pressures. However, explanations as to how tumor cells are influenced by the inflammatory tumor microenvironment over time are, to date, poorly defined. We hypothesized that prognostic biomarkers could be obtained by exploring the expression of inflammation-associated genes between early and late stage lung cancer tumor samples. more...

The presence of comorbid anxiety disorders (AD) and bipolar II disorders (BP-II) compounds disability complicates treatment, worsens prognosis, and has been understudied. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes, may be important to the pathogenesis of BP-II comorbid with AD. We aimed to clarify ALDH2 and DRD2 genes for predisposition to BP-II comorbid with and without AD. The sample consisted of 335 subjects BP-II without AD, 127 subjects BP-II with AD and 348 healthy subjects as normal control. The genotypes of the ALDH2 and DRD2 Taq-IA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR = 2.231, P = 0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed (OR = 5.623, P = 0.001) compared with normal control. Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD. more...

Heroin dependence is a multifactor disorder. We investigated the association of genetic factors and heroin-dependent temperaments to determine whether a temperament-gene interaction is involved in the pathogenesis of heroin dependence.Three hundred seventy participants (259 heroin-dependent patients and 111 healthy controls) were recruited and finished the Tridimensional Personality Questionnaire to assess personality traits (temperament). The genotypes of the aldehyde dehydrogenase 2 (ALDH2) gene and the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene using polymerase chain reactions plus restriction fragment length polymorphism analysis.Multiple logistic regression analysis showed significant main effects for novelty seeking (P ≤ 0.001) and harm-avoidance (P = 0.001) scores, and a significant interaction effect between novelty seeking and ALDH2 genotypes (P = 0.016) in heroin-dependent patients compared with controls. When stratified by the ALDH2 genotypes, only heroin-dependent patients with the *1*2 and *2*2 genotypes at ALDH2 had higher novelty-seeking scores than did controls (heroin dependence = 15.94, controls = 12.46; P ≤ 0.001).Our results provide initial evidence that the ALDH2 gene interacted with novelty seeking in heroin-dependent Han Chinese patients in Taiwan. more...

Purpose To investigate serum markers associated with radiation pneumonitis (RP) grade ≥3 in patients with lung cancer who were treated with radiation therapy. Methods and Materials Pretreatment serum samples from patients with stage Ib-IV lung cancer who developed RP within 1 year after radiation therapy were analyzed to identify a proteome marker able to stratify patients prone to develop severe RP by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Dosimetric parameters and 3 biological factors were compared. Results Serum samples from 16 patients (28%) with severe RP (grade 3-4) and 42 patients (72%) with no or mild RP (grade 0-2) were collected for analysis. All patients received a median of 54 Gy (range, 42-70 Gy) of three-dimensional conformal radiation therapy with a mean lung dose (MLD) of 1502 cGy (range, 700-2794 cGy). An m/z peak of 11,480 Da was identified by SELDI-TOF-MS, and serum amyloid A (SAA) was the primary splitter serum marker. The receiver operating characteristic area under the curve of SAA (0.94; 95% confidence interval [CI], 0.87-1.00) was higher than those of C-reactive protein (0.83; 95% CI, 0.72-0.94), interleukin-6 (0.79; 95% CI, 0.65-0.94), and MLD (0.57; 95% CI, 0.37-0.77). The best sensitivity and specificity of combined SAA and MLD for predicting RP were 88.9% and 96.0%, respectively. Conclusions Baseline SAA could be used as an auxiliary marker for predicting severe RP. Extreme care should be taken to limit the lung irradiation dose in patients with high SAA. more...

Microarray transcriptome study in cancer has been commonly used to investigate tumorigenic mechanisms. The unique growth pattern of spontaneous regression (SR) after progressive (P) growth in canine transmissible venereal tumor (CTVT) provides a valuable cancer model to study the genome-wide differences in samples between the two stages of growth. In this study, Affymetrix analysis was performed based on the canine genome to compare the gene expression profiles of CTVT P- and SR-phase tumors. A total of 459 (278 up-regulated and 181 down-regulated) genes were identified as being differentially-expressed during the SR phase by the 2-fold method. Further analysis of these genes revealed that the expression of three genes associated with IL-6 production -TIMD-4, GPNMB and PLTP - was significantly higher in SR-phase tumors than in P-phase tumors; these results were also confirmed by real time RT-PCR in tumor tissues of beagles. In addition, we found that Th17-related genes were over-expressed in the SR phase, suggesting autoimmune responses involvement in tumor regression. Although the interaction between CTVT and host immunity were partially investigated in previous studies, our results enable us to gain new insight into the genes and possible mechanisms involved in tumor regression and reveal potentially useful targets for cancer therapy. more...

// Ching-Min Lin 1, * , Yu-Ling Lin 2, 3, * , Shu-Yi Ho 3 , Pin-Rong Chen 1 , Yi-Hsuan Tsai 1 , Chen-Han Chung 1 , Chia-Hsiang Hwang 4 , Nu-Man Tsai 5, 6, * , Shey-Cherng Tzou 1, 3 , Chun-Yen Ke 1 , Jung Chang 3 , Yi-Lin Chan 7 , Yu-Shan Wang 8 , Kwan-Hwa Chi 8, * and Kuang-Wen Liao 1, 3, 9, * 1 Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan 2 Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan 3 Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan 4 Yung-Shin Pharmaceutical Industry Co., Ltd., Taichung, Taiwan 5 Department of Medical and Laboratory Biotechnology, Chung Shan Medical University, Taichung, Taiwan 6 Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan 7 Department of Life Science, Chinese Culture University, Taichung, Taiwan 8 Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 9 Graduate Institut of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan * These authors contributed equally to this work Correspondence to: Kuang-Wen Liao, email: liaonms@mail.nctu.edu.tw Keywords: biflavonoid, angiogenesis, metastasis, actin polymerization, cAMP response element-binding protein (CREB) Received: February 02, 2016 Accepted: June 29, 2016 Published: July 30, 2016 ABSTRACT 7,7”-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from Taxus x media cv. Hicksii, induces apoptotic and autophagic cell death. However, whether DMGF suppresses tumor metastasis is unclear. The aim of this study was to investigate the anti-metastatic activities of DMGF on the metastatic processes of melanoma cells in vivo and in vitro . A transwell assay showed that DMGF could effectively attenuate the motility of B16F10 cells, and the results of real-time PCR revealed that DMGF also suppressed the expressions of matrix metalloproteinase-2 (MMP-2). Moreover, DMGF did not influence tube formation but inhibited the migration of endothelial cells. Furthermore, animal models were used to monitor the effects of DMGF on tumor metastasis, and all models showed that DMGF significantly suppressed the metastatic behaviors of B16F10 cells, including intravasation, colonization, and invasion of the lymphatic duct. In addition, DMGF could also reduce the densities of the blood vessels in the tumor area in vivo. Further investigation of the molecular mechanisms of anti-metastatic activity revealed that DMGF can down-regulate the levels of key modulators of the Cdc42/Rac1 pathway to interfere in F-actin polymerization and suppress the formation of lamellipodia by reducing the phosphorylation of CREB. These data suggested that DMGF presents anti-metastatic activities in B16F10 melanoma cells. Here, we demonstrated that DMGF can inhibit the metastasis of highly invasive melanoma cancer cells through the down-regulation of F-actin polymerization. Considering these findings, DMGF may be further developed to serve as a chemoprevention drug for patients with metastatic melanoma. more...

The aim of our study was to investigate the value of the transtelephonic electrocardiogram (TTECG) monitoring system during a "blanking period" of 3 months after ablation by analyzing the frequency of atrial arrhythmias episodes and the relationship between the frequency of atrial fibrillation (AF) attacks and long-term follow-up outcomes.Ninety-two patients with AF received primary ablation and were fitted with an external loop recorder for daily and symptomatic patient-triggered detection of AF recurrence during a "blanking period," which was defined as 3 months after discharge. All patients received regularly scheduled clinical follow-up programs that included 24-hour Holter for 12 months. Atrial fibrillation recurrence was defined as an episode of AF, atrial flutter, or atrial tachycardia lasting for 30 seconds or longer, which was documented on TTECG or 24-hour Holter. After the 12th month of monitoring, patients were divided into 2 groups based on the follow-up data: a recurrence group and a nonrecurrence group.A total of 18 969 TTECGs were received, the rate of effective TTECGs was 96.1% (18 236/18 969). At the end of the blanking period, 39 (42.4%) patients with AF recurrence were recorded by TTECG monitoring, whereas 27 (29.3%) patients were recorded by electrocardiogram and 24-hour Holter monitoring (P = .032). By analyzing the TTECG diagnosis, the percentage of total AF attacks in the recurrence group was higher than in the nonrecurrence group (median: 27.8% versus 10.6%, P.01). The percentage of monthly AF attacks in the recurrence group occurred at a high level during the blanking period (sequent: 24.4%, 32.4%, and 28.1%; P = .65). There was also a certain amount of AF attacks in the nonrecurrence group during the blanking period, but the percentage of AF attacks in this group significantly decreased each month (sequent: 18.6%, 11.0%, and 4.9%; P.01).The TTECG monitoring was superior to the standard electrocardiogram and 24-hour Holter recordings in evaluating AF recurrence after ablation. Atrial arrhythmias episodes were common during the blanking period whether the long-term follow-up outcome was a success or a failure. Atrial fibrillation attacks during the blanking period did not indicate failure of ablation in long-term outcomes. However, frequent and nonsignificantly decreasing AF attacks during the blanking period indicated a high probability of failure of AF ablation in long-term follow-up outcomes. more...

Depressed activity of natural killer (NK) cells is often associated with a higher incidence of infection and tumor recurrence. Despite evidence that NK cell activity is depressed after chemotherapy, there have been no clinical trials reporting the amelioration of this side effect. ChemoYoung, a fermented soybean extract, has been shown to activate NK cells in vivo. We conducted a randomized clinical trial to examine the effect of ChemoYoung on the restoration of NK cell activity during chemotherapy. Thirty-two patients were recruited for a self-controlled, randomized, crossover chemotherapy program with 2 consecutive, identical dose intensity chemotherapy cycles, with or without the oral intake of ChemoYoung during each cycle of chemotherapy. Patients were administered ChemoYoung (MicroBio Biotech Comp, Taipei, Taiwan) for 21 days during chemotherapy. The NK cell activity, T4/T8 ratio, NK cell number, and serum interleukin (IL) 2 level on day 21 of each cycle were compared. The mean white blood cell nadir, T4/T8 (%), NK number (%), and IL-2 serum level (ng/mL) of the combined group vs the chemotherapy-alone group were 3096/ μ L vs 2404/ μ L, 35.3/15.2 vs 29.2/13.7, 19% vs 17%, and 3.2 vs 2.0, respectively (all P > .1). However, the NK activity was 13.4 ± 10.3 for the combined treatment group and 4.5 ± 3.2 for the chemotherapy-alone group ( P = .001). Natural killer cell activities were significantly reduced in patients who received chemotherapy without the adjuvant use of ChemoYoung. A trend to a better quality of life was also noted as assessed using the instrument of the European Organization for Research and Treatment of Cancer core questionnaire. more...

Tumors often target dendritic cells (DCs) to evade host immune surveillance. DC injury is reported in many rodent and human tumors but seldom in tumors of other mammals. Canine transmissible venereal tumor (CTVT), a unique and spontaneous cancer transmitted by means of viable tumor cells. CTVT causes manifold damage to monocyte-derived DCs. This cancer provides an in vivo model of cancer to study the role of monocyte-derived DCs during spontaneous regression. Using flow cytometry and real-time reverse-transcription polymerase chain reactions, we compared the expression of surface molecules on monocyte-derived DCs between normal dogs and dogs with CTVT. These markers were CD1a, CD83, costimulatory factors (CD40, CD80, and CD86), and major histocompatability complex classes I and II. In immature DCs (iDCs) and lipopolysaccharide-treated mature DCs (mDCs), the surface markers were mostly downregulated during tumoral progression and regression. The tumor lowered endocytic activity of iDCs, as reflected in dextran uptake, and decreased allogeneic mixed lymphocyte reactions of mDCs. In addition, it decreased the number of monocytes in the peripheral blood by 40%. The tumor substantially impaired the efficiency with which DCs were generated from monocytes and with which mDCs were generated from iDCs. We also found that progression-phase CTVT supernatants that were cultured for 48 h and that contained protein components killed both monocytes and DCs. Additionally, DC numbers were significantly lower in the draining lymph nodes in CTVT dogs than in normal dogs. In conclusion, CTVT caused devastating damage to monocyte-derived DCs; this might be one of its mechanisms for evading host immunity. Reestablishment of monocyte-derived DC activity by the host potentially might contribute to spontaneous tumoral regression. These findings provide insight into the extent of tumoral effects on host immune systems and responses. This information is useful for developing cancer immunotherapies. more...

Both monoamine oxidase A (MAOA) and dopamine D2 receptor (DRD2) genes have been considered as candidate genes for antisocial personality disorder with alcoholism (Antisocial ALC) [Parsian, A., 1999. Sequence analysis of exon 8 of MAO-A gene in alcoholics with antisocial personality and normal controls. Genomics. 45, 290–295.; Samochowiec, J., Lesch, K.P., Rottmann, M., Smolka, M., Syagailo, Y.V., Okladnova, O., Rommelspacher, H., Winterer, G., Schmidt, L.G., Sander, T., 1999. Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism. Psychiatry. Res. 86, 67–72.; Schmidt, L.vG., Sander, T., Kuhn, S., Smolka, M., Rommelspacher, H., Samochowiec, J., Lesch, K.P., 2000. Different allele distribution of a regulatory MAO-A gene promotor polymorphism in antisocial and anxious-depressive alcoholics. J. Neural .Transm. 107, 681–689.]. However, the association between alcoholism and MAOA or DRD2 gene has not been universally accepted [Lee, J.F., Lu, R.B., Ko, H.C., Chang, F.M., Yin, S.J., Pakstis, A.J., Kidd, K.K., 1999. No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Alcohol. Clin. Exp. Res. 23, 592–599.; Lu, R.B., Lin, W.W., Lee, J.F., Ko, H.C., Shih, J.C., 2003. Neither antisocial personality disorder nor antisocial alcoholism association with MAOA gene among Han Chinese males in Taiwan. Alcohol. Clin. Exp. Res. 27, 889–893.]. Since dopamine is metabolized to 3,4-dihydroxyphenyl-acetaldehyde (DOPAL) via monoamine oxidase (MAO) [Westerink, B.H., de Vries, J.B., 1985. On the origin of dopamine and its metabolite in predominantly noradrenergic innervated brain areas. Brain. Res. 330, 164–166.], the interaction between MAOA and DRD2 genes might be related to Antisocial ALC. The present study aimed to determine whether Antisocial ALC might be associated with the possible interactions of DRD2 gene with MAOA gene. Of the 231 Han Chinese subjects who were recruited for the study, 73 participants were diagnosed with Antisocial ALC and 158 subjects were diagnosed with antisocial personality disorder without alcoholism (Antisocial Non-ALC). The DRD2 TaqI A and MAOA-uVNTR (variable number of tandem repeat located upstream) polymorphisms were not found to be associated with Antisocial ALC. However, an association between DRD2 TaqI A polymorphisms and Antisocial ALC was shown only after stratification for the MAOA-uVNTR 4-repeat polymorphism. Additionally, after multiple logistic regressions, we found that, under stratification of MAOA-uVNTR 4-repeat polymorphism and in comparison with the DRD2 A1/A1 genotype as a reference group, the DRD2 A1/A2 genotype has a possible protective effect against alcoholism in individuals with antisocial personality disorder (ASPD). We concluded that the possible interactions between MAOA-uVNTR polymorphism and DRD2 TaqI A polymorphism might be related to Antisocial ALC among Han Chinese men in Taiwan. more...

Background The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs. Methods The CT26 murine colorectal cancer model was used in this investigation. The inhibition of growth of the tumor and the systemic anti-tumor immune response were measured. The tumor was heated to a core temperature of 42 °C for 30 min. The matured synergetic DCs were intratumorally injected 24 h following mEHT was applied. Results mEHT induced significant apoptosis and enhanced the release of heat shock protein70 (Hsp70) in CT26 tumors. Treatment with mEHT-DCs significantly inhibited CT26 tumor growth, relative to DCs alone or mEHT alone. The secondary tumor protection effect upon rechallenging was observed in mice that were treated with mEHT-DCs. Immunohistochemical staining of CD45 and F4/80 revealed that mEHT-DC treatment increased the number of leukocytes and macrophages. Most interestingly, mEHT also induced infiltrations of eosinophil, which has recently been reported to be an orchestrator of a specific T cell response. Cytotoxic T cell assay and ELISpot assay revealed a tumor-specific T cell activity. Conclusions This study demonstrated that mEHT induces tumor cell apoptosis and enhances the release of Hsp70 from heated tumor cells, unlike conventional hyperthermia. mEHT can create a favorable tumor microenvironment for an immunological chain reaction that improves the success rate of intratumoral DC immunotherapy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1690-2) contains supplementary material, which is available to authorized users. more...

A phase 1 study was conducted to assess the safety and immunologic response induced by direct injection of autologous immature dendritic cells (DCs) into tumor under radiotherapy in advanced hepatoma patients. Patients with advanced/metastatic stage hepatoma not suitable for surgery or transarterial embolization were enrolled. Groups of patients received two vaccinations. Each vaccination consisted of intratumoral injections of autologous immature DCs in four dose cohorts of 5 x 10(6), 1.5 x 10(7), 3 x 10(7), and 5 x 10(7) cells 2 days after a single fraction of conformal radiotherapy of 8 Gy. The second vaccination was performed 3 weeks later. Of the 14 patients entered, 12 completed two cycles of vaccination. The treatment was well tolerated at any of the dose levels. Six patients had mild transient fever (grade 1-2) with chill reactions, three patients developed grade 1 fatigue, and one patient developed mild myalgia and arthralgia after DC injections. There was no evidence of clinically manifested autoimmune disease. There were two partial responses and four minor responses. A decrease in the alpha-fetoprotein (AFP) level of more than 50% was found in three patients. Ten patients had completed immunologic response evaluation 2 weeks after the second cycle of vaccination. The AFP-specific immune response was evident in eight patients examined by cytokine release assay and in seven patients by ELISPOT assay. Six patients showed an increased NK cell cytotoxic activity after vaccination. These data suggest that the combination of intratumoral injection of DCs and conformal radiotherapy is safe and can induce tumor-specific and innate immunity. more...

Major depressive disorder (MDD), one of the most common psychiatric disorders in the world, is a serious, recurrent and chronic mental disorder, which is associated with significant psychosocial disability and economic burden. Until recently, short-term effectiveness of antidepressants has been measured in terms of patients' response to the medications in significantly reduced depressive symptoms. Remission, a long-term elimination of symptoms and the restoration of normal functioning, has become the primary outcome of therapy. In the current study, the efficacy of three frequently prescribed antidepressants, venlafaxine (75-225 mg/day), paroxetine (20 mg/day) and milnacipran (100 mg/day), used in treating 249 MDD patients with Hamilton Rating Scale of Depression (HRSD₁₇) scores higher than 16 was compared. Each patient was evaluated at week 0, 1, 2, 4, 8, 12, 16, 20 and 24 in a 24-week open-label study. Eighty-two patients took venlafaxine, 97 took paroxetine and 70 patients took milnacipran. No significant differences were found between the three groups in the response condition (HRSD₁₇ scores decreased more than 50%) after 24 weeks of follow-up. For remission, the paroxetine was the least efficacious medication than either the milnacipran (HRSD₁₇ ≤ 7) or the venlafaxine (HRSD₁₇ ≤ 5) by the last observation carried forward (LOCF) analysis. Our results suggest that the absence of depressive symptoms alone may not be an indicator for MDD remission, but the duration of absent depressive symptoms may be a better indicator. more...

Memantine, a noncompetitive N-methyl-d-aspartate receptor antagonist with a mood-stabilizing effect, and an association between bipolar disorder and proinflammatory cytokine levels have been reported. Whether adding-on memantine would reduce cytokine levels and is more effective than valproic acid (VPA) alone in bipolar II disorder was investigated. A randomized, double-blind, controlled, 12-week study was conducted. Patients undergoing regular VPA treatments were randomly assigned to a group: VPA + memantine (5 mg/d) (n = 106) or VPA + placebo (n = 108). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical response. Symptom severity, plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-8, and IL-1 levels were examined during weeks 0, 1, 2, 4, 8, and 12. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Tumor necrosis factor α levels were significantly lower in the VPA + memantine group than in the VPA + placebo group (P = 0.013). Posttreatment HDRS and YMRS scores decreased significantly in both groups, but not significant, nor was the other between-group cytokine level difference pretreatment and posttreatment. The HDRS score changes were significantly associated with IL-6 (P = 0.012) and IL-1 (P = 0.005) level changes and changes in YMRS score changes with TNF-α (P = 0.005) level changes. Treating bipolar II depression with VPA + memantine may improve the plasma TNF-α level. However, adding-on memantine may not improve clinical symptoms or cytokine levels other than TNF-α. Clinical symptoms may be correlated with certain cytokines. more...

ObjectiveTo analyze the effect of intestinal function–recovering decoction on multiple organ dysfunction syndrome in rats, and to investigate a novel solution to multiple organ dysfunction syndrome.MethodsMultiple organ dysfunction syndrome was induced in 60 Sprague–Dawley rats by intestinal ischemia–reperfusion combined with cecal ligation and puncture. Then these rats were intragastrically administered physiological saline (group I, n=20), ampicillin (group II, n=20) or intestinal function–recovering decoction (group III, n=20). After treatment, serum malondialdehyde and superoxide dismutase levels were compared among three groups. Simultaneously, bacterial culture of various organ tissues was performed and bacterial and endotoxin translocation were observed.ResultsCompared with group I, serum malondialdehyde, alanine aminotransferase and aspartate aminotransferase levels were significantly decreased (all P0.05). The rate of bacterial translocation in the groups II and III was significantly lower than in the group I (P0.05).ConclusionsIntestinal function–recovering decoction can significantly reduce endotoxin and bacterial translocation and stabilize enteral oxidative–antioxidative balance. more...

UNLABELLED:Inflammation is thought to be involved in the pathophysiology of bipolar disorder (BP) and metabolic syndrome. Prior studies evaluated the association between metabolic profiles and cytokines only during certain mood states instead of their changes during treatment. We enrolled drug-naïve patients with BP-II and investigated the correlation between changes in mood symptoms and metabolic indices with changes in plasma cytokine levels after 12 weeks of pharmacological treatment. Drug-naïve patients (n = 117) diagnosed with BP-II according to DSM-IV criteria were recruited. Metabolic profiles (cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI) and plasma cytokines (TNF-α, CRP, IL-6, and TGF-β) were measured at baseline and 2, 8, and 12 weeks post-treatment. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the intervention. Changes in plasma CRP were significantly associated with changes in BMI (P = 1.7E-7) and triglyceride (P = 0.005) levels. Changes in plasma TGF-β1 were significantly associated with changes in BMI (P = 8.2E-6), cholesterol (P = 0.004), and triglyceride (P = 0.006) levels. However, changes in plasma TNF-α and IL-6 were not associated with changes in any of the metabolic indices. Changes in Hamilton Depression Rating Scale scores were significantly associated with changes in IL-6 (P = 0.003) levels; changes in Young Mania Rating Scale scores were significantly associated with changes in CRP (P = 0.006) and TNF-α (P = 0.039) levels. Plasma CRP and TGF-β1 levels were positively correlated with several metabolic indices in BP-II after 12 weeks of pharmacological intervention. We also hypothesize that clinical symptoms are correlated with certain cytokines. These new findings might be important evidence that inflammation is the pathophysiology of clinical symptoms and metabolic disturbance in BP-II. TRIAL REGISTRATION:ClinicalTrials.gov NCT01188148. more...

Memantine is a noncompetitive NMDA receptor antagonist. As an augmenting agent, it has an antidepressant-like and mood-stabilizing effect. Memantine also reduces binge eating episodes and weight. We investigated whether memantine added on to valproate (VPA) is more effective than VPA alone for treating BP-II depression and improving the patient's metabolic profile. This was a randomized, double-blind, controlled study. BP-II patients undergoing regular VPA treatments were randomly assigned to one of two groups: VPA plus either add-on [1] memantine (5 mg/day) ( n = 62) or [2] placebo ( n = 73) for 12 weeks. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate clinical response. Height, weight, fasting serum glucose, fasting total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were followed regularly. Multiple linear regressions with generalized estimating equation methods were used to analyze the effects of memantine on clinical performance. There were no significant differences in pre- and post-treatment YMRS and HDRS scores between the VPA + memantine and VPA + placebo groups. Although there were no significant differences in the pre- and post-treatment values of most metabolic indices between the two groups, there was a significant increase of HDL-C ( p = 0.009) in the VPA + memantine group compared with the VPA + placebo group. This increase remained significant even after controlling for body mass index (BMI) ( p = 0.020). We conclude that add-on memantine plus VPA treatment of BP-II depression increases the blood level of HDL-C even in the absence of change in affective symptoms. Trial registration : NCT01188148 ( https://register.clinicaltrials.gov/ ), Trial date was from 1st August, 2008 to 31st July, 2012 in National Cheng Kung University and Tri-Service General Hospital. more...

Bipolar disorder (BP), especially bipolar II disorder (BP-II), is highly comorbid with anxiety disorder (AD). Monoaminergic dysfunction has been implicated in the pathogenesis of BP, it may be important to investigate genes such as the catechol-O-methyltransferase (COMT), involved in monoamine metabolism and brain-derived neurotrophic factor (BDNF) genes, modulating the monoamine system. We therefore examined the association of the COMT Val158Met and BDNF Val66Met polymorphisms with BP-II with and without comorbidity of AD, and possible interactions between these genes. Seven hundred and seventy-one participants were recruited: 314 with bipolar-II without AD, 117 with bipolar-II with AD, and 340 healthy controls. The genotypes of the COMT and BDNF polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant effect of the COMT and the BDNF polymorphisms, and a significant interaction effect for the Val/Val genotypes of the BDNF Val66Met polymorphism and the COMsT Val158Met Val/Met and Met/Met genotypes (P = 0.007, 0.048) discriminated between BP-II without AD patients and controls. Our findings provide initial evidence that the COMT and BDNF genes interact in bipolar-II without AD. Our findings suggest the involvement of dopaminergic pathway in the pathogenesis of bipolar-II. more...

Background: Determinants of functional mitral regurgitation (FMR) severity after acute anterior myocardial infarction (MI) remained unclear. Our aim was to: (1) test whether LV dyssynchrony upon real time three-dimensional echocardiography (RT-3DE) is independently associated with FMR severity; and (2) to investigate the role of regional systolic dyssynchrony index (SDI) in identifying FMR severity. Methods: RT-3DE was successfully performed on 64 consecutive patients following acute anterior MI with a narrow QRS complex ( more...

Background Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) is a frequently used technique for cancer biomarker research. The specificity of biomarkers detected by SELDI can be influenced by concomitant inflammation. This study aimed to increase detection accuracy using a two-stage analysis process. Methods Sera from 118 lung cancer patients, 72 healthy individuals, and 31 patients with inflammatory disease were randomly divided into training and testing groups by 3:2 ratio. In the training group, the traditional method of using SELDI profile analysis to directly distinguish lung cancer patients from sera was used. The two-stage analysis of distinguishing the healthy people and non-healthy patients (1st-stage) and then differentiating cancer patients from inflammatory disease patients (2nd-stage) to minimize the influence of inflammation was validated in the test group. Results In the test group, the one-stage method had 87.2% sensitivity, 37.5% specificity, and 64.4% accuracy. The two-stage method had lower sensitivity (> 70.1%) but statistically higher specificity (80%) and accuracy (74.7%). The predominantly expressed protein peak at 11480 Da was the primary splitter regardless of one- or two-stage analysis. This peak was suspected to be SAA (Serum Amyloid A) due to the similar m/z countered around this area. This hypothesis was further tested using an SAA ELISA assay. Conclusions Inflammatory disease can severely interfere with the detection accuracy of SELDI profiles for lung cancer. Using a two-stage training process will improve the specificity and accuracy of detecting lung cancer. more...

Aims To investigate the appropriate duration of head-up tilt test (HUTT) needed to induce a positive reaction in patients with suspected vasovagal syncope. Methods and results Consecutive patients referred to the syncope unit of our centre for recurrent unexplained syncope were studied. The HUTT included a 30 min passive basic phase and a 20 min sublingual nitroglycerin provocation phase if syncope did not develop during the passive phase. We studied 773 consecutive patients, and 427 (55.2%) patients had a positive HUTT, including 46 patients (10.8%) during the passive basic phase and 381 patients (89.2%) during the nitroglycerin provocation phase. During the basic phase, positive reaction appeared at 7.5 min, and the percentage of positive cases increased with the duration of the test, reaching a peak (20.9%) at 22.5 min, and then decreasing gradually. Most positive reactions (96.1%) occurred between 10 and 25 min during the basic phase. During the nitroglycerin provocation phase, however, the percentage of positive reactions increased rapidly after sublingual nitroglycerin, peaking (35.7%) at 10 min, followed by a sharp decline. Most positive reactions (96.1%) occurred in the first 15 min of the provocation phase. Conclusion The HUTT was a useful diagnostic test in patients with suspected vasovagal syncope, and sublingual nitroglycerin increased the rate of positive reactions. The appropriate duration for HUTT required at least 25 min during the passive basic phase and 15 min during the nitroglycerin provocation phase. more...

Background Chemokines play multiple roles in the development and progression in a variety of tumors. Chemokine (C-X-C motif) ligand 7 (CXCL7) has been found associated with pro-inflammatory responses, but its role in cancer growth remains unclear. Our previous study showed that R phase tumor infiltrating lymphocytes (TILs) produced large amounts of interleukin (IL)-6 which antagonized transforming growth factor (TGF)-β derived from CTVT to diminish the immune-suppressive microenvironment. Now we intend to determine the expression pattern of CXCL7 and the role of IL-6/TGF-β in CXCL7 induction during spontaneous progressive (P) and regressive (R) phases in canine transmissible venereal tumor (CTVT). Results We have demonstrated that CXCL7 expressed at high level in P phase and down-regulated in R phase by western blot and real-time PCR. This suggested that CXCL7 expression was negatively correlated with the tumor growth. Co-culturing TILs with CTVT cells was found to reduce CXCL7 expression, while adding IL-6 blocking antibody reversed it. Moreover, in P phase CTVT, while IL-1β and TGF-β had no obvious effect on CXCL7 expression, IL-6 was found significantly to reduce CXCL7 expression in a dose-dependent manner. The mRNA expression results of CXCL7 receptor, CXCR2, further confirmed the effects of IL-6 concentration on the CXCL7 expression. Conclusion CXCL7 overexpression might be associated with the progressive growth of CTVT. The results shown here also suggest the role of CXCL7 in cancer development and the potential as the anti-cancer therapeutic target. more...

Chemoresistance is the main obstacle of successful cancer therapy. Autophagy may either enhance cancer cell death or activate chemoresistance. Simultaneous pushing and blocking of autophagy may be a valid strategy for overcoming drug resistance and improving responses. We hypothesized that simultaneous forcing hepatoma cells synchronized in a pro-autophagic status by rapamycin while blocking the final autophagic pathway by chloroquine is an example of synthetic lethality in synergism. Co-administration of the chemotherapeutic agents with rapamycin and chloroquine in 3 hepatoma cell lines have all demonstrated synergistic effects including 5-fluorouracil, navelbine, taxotere or cisplatin. Increasing doses of rapamycin and chloroquine resulted in a significant decrease of ED50 of different chemodrugs. Althrough hepatoma cell lines expressed difference status of autophage during various chemodrug treatments, co-administration of rapamycin and chloroquine could synchronize them on the pro-autophagic status while preveting them ensuring to the final autophagic status in all cell line tested. The combination of rapamycin and chloroquine and chemotherapeutic agents resulted in increased apoptotic cell death compared to chemotherapeutic agents alone. All of the observed synergistic chemosensitization effect from combination of chloroquine and rapamycin is more obvious than either agent alone. In vivo experiments are underway. If these synergistic effects can be reproduced in vivo, the combination of rapamycin and chloroquine may provide a valid reversing resistance strategy in treatment refractory cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5611. doi:1538-7445.AM2012-5611 more...