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Cisplatin induces anorexia, weight loss, loss of adipose tissue, skeletal muscle atrophy, and serious adverse effects that can cause premature termination of chemotherapy. The aim of this study was to use an animal model to assess cisplatin therapy (3 cycles) with and without d-methionine to investigate its protective effects on cisplatin-induced anorexia and skeletal muscle wasting. Wistar rats were divided into 3 groups and treated as follows: saline as control (group 1), intraperitoneal cisplatin once a week for 3 weeks (group 2), and intraperitoneal cisplatin once a week for 3 weeks plus oral administration of d-methionine (group 3). Tissue somatic index (TSI), gastric emptying index (GEI), and feeding efficiency were measured. Both hepatic lipid metabolism and muscle atrophy-related gene expressions and C2C12 myotubes were determined by polymerase chain reaction. Micro–computed tomography (micro-CT) was used to conduct assessment of bone microarchitecture indices. Pathological changes of the gastric mucosa were assessed by hematoxylin and eosin staining after euthanizing the animals. d-Methionine increased food intake, weight gain, gastric emptying, and feeding efficiency, as well as decrease stomach contents, after cisplatin injections. Cisplatin caused shortening of myofibers. Cisplatin-induced muscle mass wasting was mediated by the elevation of mRNA expressions of MAFbx and MuRF-1 in ubiquitin ligases in muscle tissue homogenate. The mRNA expressions of MyoD and myogenin, markers of muscle differentiation, declined following cisplatin administration. The administration of d-methionine not only led to significant improvements in myofiber diameter and cross-sectional fiber areas but also reversed muscle atrophy-related gene expression. However, there were no significant changes in stomach histology or microarchitecture of trabecular bone among the study groups. The results indicate that d-methionine has an appetite-enhancing effect and ameliorates cisplatin-induced adipose and muscle tissue loss during cisplatin-based chemotherapy.

Lung cancer is the leading cause of cancer death. The endothelin-1 (EDN1)/endothelin A receptor (EDNRA) axis may directly contribute to tumor growth and indirectly modulate tumor–host interactions in various tumors. Since the genetic background between EDN1/EDNRA and non-small cell lung cancer (NSCLC) remains unknown. In this study, the association of genotypic polymorphisms in EDN1 and EDNRA with NSCLC was investigated. 388 patients with NSCLC and 396 healthy controls recruited from the China Medical Hospital in Taiwan were genotyped by a PCR-RFLP method. Results: Overall, the distribution of the genotype frequencies of EDN1 rs5370 G/T and EDNRA rs5333 T/C were significantly different between the lung cancer patients and the healthy controls, and also different between patients with lung cancers of various stages. Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen for individuals with EDN1 rs5370 TT genotype against GG/GT genotypes (an OR of 4.22, 95% CI 2.68-7.02, p Conclusions: A significant association between the EDN1 rs5370 G/T and EDNRA rs5333 T/C genetic polymorphisms and the susceptibility to NSCLC was demonstrated. Also, these two polymorphisms were associated with the severity of lung cancer. The EDN1 rs5370 TT and EDNRA rs5333 CC genotypes have a promotive effect for lung cancer development and progression.

Background The aim of this study was to evaluate the relations of chemokine CXCL12, previously known as stromal cell-derived factor-1 (SDF1), and its receptor, CXCR4, gene variants on non-small cell lung cancer (NSCLC) risk and disease severity. Methods Through a case–control study design, genomic DNA samples of 247 NSCLC patients and 328 age and sex-matched controls were subjected to polymerase chain reaction-restriction fragment length polymorphism analysis. The validity of this technique was proven by direct sequencing of amplified products. Statistical analyses were conducted to explore the contribution of polymorphism of the CXCL12/SDF1 gene and CXCR4, in the susceptibility to and prognosis of NSCLC. Results Overall, the genotype frequencies of CXCL12/SDF1 gene and CXCR4, were significantly different between lung cancer patients and controls (p

Background Urokinase plasminogen activating (uPA) system is implicated in neoplastic progression. High tissue levels of uPA system components correlate with a poor prognosis in lung cancer. The present study examined the single nucleotide polymorphisms (SNPs) of uPA and the corresponding receptor, uPAR, for exploring their roles in non-small cell lung cancer (NSCLC). Methods The allele frequencies and genotype distributions of uPA rs4065 C/T and uPAR rs344781 (− 516 T/C) among 375 NSCLC cases and 380 healthy controls were examined using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis. Putative association between the above SNPs and clinicopathological characteristics of NSCLC were also analyzed. Results The genotype frequencies of the variant homozygotes of uPA and uPAR were significantly different between NSCLC and control subjects. Significant association was also observed between the examined genotypes and disease stage of NSCLC. Logistic regression analysis revealed that individuals with uPA rs4065 TT genotype have higher odds ratios (ORs) for lung cancer. Whereas, subjects with uPAR-344781 CC genotype have lower ORs for lung cancer. The patients carrying a homozygous TT genotype at uPA rs4065, or at least a T allele at uPAR-344781 (− 516), had a tendency to develop advanced disease. Conclusions Our results revealed that genetic polymorphisms of the uPA rs4065 C/T and uPAR rs344781 (− 516 T/C) were associated with the susceptibility and severity of NSCLC.

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease influenced by genetic and environmental factors, particularly cigarette smoking. Although cigarette smoke may be directly mutagenic, polymorphisms in the genes controlling acquired somatic mutations may also contribute, at least to some extent, to the observed differing susceptibilities to COPD. To investigate the involvement of genetic polymorphisms of p53 and p21 in the pathogenesis of COPD, the authors performed a case-control study involving 206 subjects with COPD and 210 healthy smokers as control subjects.Polymorphisms of p53 and p21 genes were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique on genomic DNA isolated from peripheral lymphocytes. The distribution of the p53 and p21 polymorphisms in healthy subjects and COPD patients was examined and compared using the Pearson X2 test. Significance was accepted at P0.05. Odds ratios (ORs) and 95% confidence intervals (CIs) of each specific genotype were calculated using logistic regression analysis to quantitatively assess the degree of association observed.The distribution frequencies of genotypes of p53 codon 72 and p21 codon 31 were significantly different between the COPD and the control groups. Higher ORs for COPD were seen for persons with p53 Pro/Pro or Pro/Arg genotypes against Arg/Arg genotype [OR = 2.35, 95% CI 1.27-4.39, P = 0.008], or p21 Arg/Arg and Arg/Ser genotypes against Ser/Ser genotype [OR = 2.07, 95% CI 1.06-4.05, P = 0.033].The polymorphisms of p53 and p21 were significantly associated with the occurrence of smoking-related COPD in Taiwan Chinese patients.

Background The relationship between bacterial etiology and serum cytokine levels in patients with severe community-acquired pneumonia (CAP) without response to initial empiric treatment remains unclear. This study investigated the bacterial etiology, outcomes, and bronchoalveolar and systemic cytokines (interleukin [IL]-1β, IL-8, IL-10) in these patients. Methods This hospital-based study enrolled 47 consecutive patients without response to initial empiric treatment and requiring mechanical ventilation due to severe CAP between July 1, 2000 and October 31, 2001, in a respiratory intensive care unit of a 1200-bed teaching hospital in central Taiwan. Bronchoalveolar lavage (BAL) was performed within 3 days after hospitalization. BAL fluid was processed for quantitative bacterial cultures. Blood samples were taken just before BAL, and the levels of both BAL and serum cytokines were measured. Results The most common pathogens isolated were Pseudomonas aeruginosa (22.5%) and Klebsiella pneumoniae (25%). Patients with a K. pneumoniae isolate ( w = 10) had significantly higher levels of IL-1β in BAL fluid and significantly higher levels of IL-10 in serum and BAL fluid than patients with other etiologies. Non-survivors had higher levels of serum IL-8 (p = 0.001), serum IL-10 (p 0.001) and BAL IL-10 (p = 0.039) than survivors. Marked increases in local and systemic cytokine expression (IL-8 and IL-10) were noted in rapidly fatal cases. Conclusion P. aeruginosa and K. pneumoniae are the most common causes of CAP requiring mechanical ventilation in Taiwan. Cytokine patterns in the BAL fluid and serum of patients with severe CAP due to K. pneumoniae showed significant elevations compared to other pathogens. Bronchoalveolar and systemic cytokine levels (especially IL-10) predicted mortality. These findings suggest the need for a clinical trial to determine how immunomodulating therapy might affect cytokine profiles and clinical outcome.

Background Correlation between p53 autoantibodies (p53 Abs) titers and the efficacy of Taiwanese lung cancer patients undergoing chemotherapy has never been investigated. Our present study aimed at evaluating putative possibility of using p53 Abs levels as a model system to monitor effect of chemotherapy and prognosis prediction of lung cancer. Methods The prevalence of p53 Abs in lung cancer patients and temporal alteration of p53 Abs titers in lung cancer patients carrying p53 Abs were investigated by using ELISA and Western blot analysis. Results p53 Abs was detected in 17 of 277 (6.14%) lung cancer patients, the positivity of p53 Abs in patients with small cell lung carcinoma and non-small cell lung carcinoma was 4.88% and 6.36%, respectively. No significant association between p53 Abs and patients' clinical manifestations was found. Titer of p53 Abs was decreased in 6 of 17 p53 Abs-carrying patients after chemotherapy. However, the decreasing p53 Abs titers were not correlated with patients' survival or chemotherapeutic efficacy. Conclusions The prevalence of p53 Abs in Taiwanese lung cancer is much lower than that in Caucasians. It is unlikely that p53 Abs titer could be a monitoring indicator for the chemotherapeutic efficacy or a prognosis indicator of lung cancer.

Objectives. To evaluate prospectively the prognostic power of urinary nuclear matrix protein-22 (NMP-22) for bladder cancer in Taiwanese screening and surveillance settings. Methods Single voided urine samples were obtained from 68 healthy individuals, 303 patients with benign urothelial diseases, and 28 patients with urogenital tumors. The NMP-22 levels in the urine samples were measured using enzyme-linked immunosorbent assay methods. Results The median NMP-22 level in healthy individuals and patients with benign and malignant disease was 5.9, 4.8, and 7.4 U/mL, respectively. The positive NMP-22 rate in healthy individuals and patients with benign and malignant disease was 4.4%, 17.2%, and 50%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value was 50%, 82.8%, 21.2%, and 94.7%, respectively, using 7.5 U/mL as the cutoff value. Conclusions Our data demonstrated that NMP-22 is not a good diagnostic tool for screening or follow-up surveillance of bladder cancer owing to its low sensitivity and positive predictive value. Nevertheless, it could be adopted as a tool to rule out the possibility or risk of developing bladder cancer because of its high negative predictive value in our study.

A mass hepatitis B vaccination program began in Taiwan in 1984. In order to determine the immune status of hepatitis B virus (HBV) infection among preschool children, a total of 25 kindergartens in 20 townships and metropolitan precincts in central Taiwan were randomly selected through stratified sampling. Serum specimens of 2130 healthy preschool children aged 2–6 years old were screened for the HBV markers and liver function in 1996. HBV surface antigen (HBsAg), antibody against HBsAg (anti-HBs) and antibody against HBV core antigen (anti-HBc) were tested by reverse passive hemagglutination (RPHA), enzyme immunoassay (EIA) and radioimmunoassay (RIA) using commercial kits. HBV vaccination rate of the preschool children was 98%, and complete vaccination rate (three or four doses of HBV vaccine) was 94%. The HBsAg seropositive rate was 4.5% among incomplete vaccinees and 1.3% among complete vaccinees. The anti-HBs was detectable in 1637 of 2000 complete vaccinees (81.9%) and in 53 of 88 incomplete vaccinees (60.2%). The overall prevalence rate of anti-HBc was 2.4% (52 of 2130). The older the age, the lower the anti-HBs seropositive rate. The anti-HBs seropositve rates for complete vaccinees were 100% at 2 years old and 75% at 6 years old. There were no significant differences in HBsAg-seropositive rates and anti-HBs-seropositive rates among different residential areas or ethnic groups. There were three children who were seropositive on HBsAg, anti-HBs and anti-HBc, whether they were infected by the vaccine-induced escape mutant of HBV deserves scrutiny.

Objective: We analyzed autoantibodies against tumor-associated antigens (TAAs) in the serum of patients with endometrioma and healthy controls to determine whether autoantibodies can be accurate biomarkers for the diagnosis of ovarian endometrioma. Methods: Serum samples were obtained from 56 patients with endometriosis and 66 healthy women who served as normal controls. The titers of antibodies against a panel of eight TAAs were analyzed using enzyme-linked immunosorbent assay. Results: We found that the serum IGFII mRNA-binding protein 1 (IMP1) autoantibody and cyclin B1 autoantibody could discriminate between healthy controls and endometriosis patients (AUC–ROC 0.777; 95% confidence interval [CI] 0.694–0.860, P

Objectives The aim of this study was to determine whether cytokine expression (interleukin [IL]-1 β , IL-6, IL-8, IL-10, and tumor necrosis factor [TNF]- α ), C-reactive protein, and endotoxins on the first day of intensive care unit (ICU) admission are associated with hospital mortality in severe community-acquired pneumonia (CAP). Design This was a prospective study with bronchoalveolar lavage (BAL) and blood sampling. Setting This study was carried out in a 44-bed medical ICU of a 1700-bed university hospital. Patients Participants included 112 mechanically ventilated patients with severe CAP. Interventions Serum and BAL fluid IL-1 β , IL-6, IL-8, IL-10, TNF- α , C-reactive protein, and endotoxins on the first day of ICU admission were obtained. Measurements and Main Results The concentrations of TNF- α in BALF and IL-6, IL-8, IL-10, and TNF- α in serum were higher in nonsurvivors than in survivor patients with CAP. Of these 112 patients with severe CAP (39%), 44 developed acute respiratory distress syndrome (ARDS); these patients seemed to have higher serum IL-6, IL-8, and IL-10 levels than did the non-ARDS group. Furthermore, in the ARDS population, we found that the endotoxin levels in the BAL fluid were higher in the survival than in the nonsurvival group and BAL fluid concentrations of IL-6, IL-8, and IL-1 β and sera levels of IL-6 and IL-10 were lower in the survival than in the nonsurvival group, and they were associated with a high negative predictive value. Conclusions Serum and BAL fluid levels of the studied cytokines on admission may provide valuable prognostic information for patients with severe CAP.

©2008 Elsevier & Formosan Medical Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Divisions of 1Chest Medicine and 6Critical Care and Respiratory Therapy, Department of Internal Medicine, and 3Department of Nursing, Taichung Veterans General Hospital, 2Central Taiwan University of Science and Technology, 4Department of Medical Technology, Chung Shan Medical University, Taichung, 5Laboratory of Epidemiology and Biostatistics, Taipei Veterans General Hospital, Taipei, and 7Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan.

Background/Purpose Acute respiratory distress syndrome (ARDS) is a serious disorder of intensive care unit patients. We evaluated the safety of continuous prone position ventilation (PRONE) and its effects on oxygenation and plasma cytokine concentrations in patients with ARDS caused by severe community-acquired pneumonia (CAP). Methods This was a prospective observational clinical study conducted in a respiratory intensive care unit of a 1200-bed medical center in central Taiwan. Twenty-two patients with severe CAP and ARDS were included. They were treated by traditional supine ventilation (SUPINE, n = 11) or PRONE (n = 11) if they met the criteria for ARDS. Patients in the PRONE group were ventilated in prone position continuously for at least 72 hours. Plasma cytokines were collected and analyzed at baseline, 24 hours and 72 hours after enrolment. Serial PaO2/FiO2 and complications were evaluated. Results Complications associated with PRONE were minor and self-limited. PRONE had higher PaO2/FiO2 ratio than SUPINE did at 48 hours after enrolment. The levels of plasma IL-6 concentration declined significantly with time in the PRONE group (p = 0.011). The levels of plasma IL-6 concentration at enrolment, 24 hours and 72 hours after enrolment also predicted the 14th day mortality of all patients. Conclusion PRONE was a safe and effective maneuver for improving oxygenation in patients with severe CAP and ARDS. PRONE also influenced IL-6 expression in patients with severe CAP.

Genetic polymorphisms in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene are involved in the regulation of expression levels and have been associated with various inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter region of the TNF-alpha gene (-308 G/A and -238 G/A) for their role in the susceptibility to and severity of non-small cell lung cancer (NSCLC), by means of an allelic association study.Using a case-control study design, lung cancer patients (n = 202) and appropriate age- and sex-matched controls recruited from the health check-up unit (n = 205) were subjected to genotype analysis for these polymorphisms, using a high-throughput allelic discrimination method.Genotype was analyzed using the polymerase chain reaction-restriction fragment length polymorphism technique with genomic DNA isolated from peripheral blood lymphocytes. Overall, the distribution of the genotype frequencies of TNF-alpha-308 A/G and -238 A/G were significantly different between the lung cancer patients and the healthy controls, and also different between patients with lung cancers of various stages (p0.0001). Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen for individuals with TNF-alpha-308 AA/GA genotypes against GG genotype (an OR of 3.75, 95% CI 2.38-5.92, p0.0001), and lower ORs were seen for individuals with TNF-alpha-238 AA/GA genotypes against GG genotype (an OR of 0.26, 95% CI 0.13-0.50, p0.0001). The patients carrying a homologous AA or heterologous GA genotype at TNF-308 (p = 0.017), or a homologous GG genotype at TNF-238 (p = 0.001), had a tendency to advanced disease.A significant association between the 308 G/A and 238 G/A polymorphisms in the promoter region of TNF-alpha and the susceptibility to lung cancer was demonstrated. Also, these two polymorphisms were associated with the severity of lung cancer. The -308 A allele has a promotive effect for lung cancer development and progression, whereas the -238 A allele has a protective function against lung cancers.

To assess the relationship between concentrations of bronchoalveolar cytokines and bacterial burden (quantitative bacterial count) in intubated patients with a presumptive diagnosis of community-acquired pneumonia.A cross-sectional and clinical investigation. SETTING Medical/surgical and respiratory intensive care unit of a tertiary 1,200-bed medical center.According to the time course of community-acquired pneumonia at the time of study with bronchoalveolar lavage, 69 mechanically ventilated patients were divided into three subgroups: primary (n = 11), referral (n = 23), and treated (n = 35) community-acquired pneumonia.Bronchoalveolar lavage was performed in the most abnormal area on chest radiograph by fiberoptic bronchoscope. Bronchoalveolar lavage fluid was processed for quantitative bacterial culture. The concentrations of bronchoalveolar lavage cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interleukin-8, and interleukin-10) also were measured.Thirty-two patients had a positive bacterial culture (bronchoalveolar lavageor = 10 colony-forming units/mL)., and made up 76% of pathogens recovered at high concentrations. The concentrations of bronchoalveolar lavage interleukin-1 beta were 199.1 +/- 32.1 and 54.9 +/- 13.0 pg/mL (mean +/- se) in the patients with positive and negative bacterial culture, respectively (p.001). Bronchoalveolar lavage interleukin- 1 beta was significantly higher in the patients with a high bacterial burden (p.001), with mixed bacterial infection (p.001), and with pneumonia (p.001), compared with values in patients without these features. The relationship between bacterial load and concentrations of bronchoalveolar lavage interleukin-1 beta was very strong in the patients with primary and referral community-acquired pneumonia but was borderline in treated community-acquired pneumonia.The common pathogens were similar to the core pathogens of hospital-acquired pneumonia, probably due to antibiotic effects, delayed sampling, and superimposed nosocomial infection. Since the concentration of bronchoalveolar lavage interleukin-1 beta was correlated with bacterial burden in the alveoli, it may be a marker for progressive and ongoing inflammation in patients who have not responded to pneumonia therapy and who have persistence of bacteria in the lung.