The Clinical Application of Anti-CCP in Rheumatoid Arthritis and Other Rheumatic Diseases

Rheumatoid arthritis (RA) is a common rheumatic disease in Caucasians and in other ethnic groups. Diagnosis is mainly based on clinical features. Before 1998, the only serological laboratory test that could contribute to the diagnosis was that for rheumatoid factor (RF). The disease activity markers for the evaluation of clinical symptoms or treatment outcome were the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). As a matter of fact, the diagnosis of early RA is quite impossible, as the clinical criteria are insufficient at the beginning stage of the disease. In 1998, Schelleken reported that a high percentage of RA patients had a specific antibody that could interact with a synthetic peptide which contained the amino acid citrulline. The high specificity (98%) for RA of this new serological marker, anti-cyclic citrullinated antibody (anti-CCP antibody), can be detected early in RA, before the typical clinical features appear. The presence or absence of this antibody can easily distinguish other rheumatic diseases from RA. Additionally, the titer of anti-CCP can be used to predict the prognosis and treatment outcome after DMARDs or biological therapy. Therefore, with improvement of sensitivity, the anti-CCP antibody will be widely used as a routine laboratory test in the clinical practice for RA

Primary temporal bone angiosarcoma: a case report.

We present a rare case of temporal bone angiosarcoma diagnosed in a 26-year-old female patient at 36 week of pregnancy. The patient was referred with a 2 months history of left otalgia and tinnitus with a tender swelling above the mastoid. Cranial imaging studies showed a 7 x 5 x 4 cm hypervascularized mass located in the left middle fossa with lysis of the temporal bone and extension to the subcutis. After the baby was delivered by caesarean section, the patient entered the oncology protocol. Selective embolization of the feeding vessels was followed by gross total surgical resection using a combined supra- and infra-tentorial approach. Pathological findings were those of a poorly differentiated, highly malignant sarcoma with a large epitheloid component and immunohistochemical evidence of endothelial differentiation (CD31, Factor VIII related antigen, CD34), consistent with an angiosarcoma with epitheloid features. No extra-cranial tumor was found after extensive staging. The patient received adjuvant radiotherapy followed by a course of chemotherapy consisting of 6 cycles of paclitaxel. At 15 months follow-up, she developed multiple distant metastasis to a left postauricular lymph node and to the lungs and ribs. The patient was given a second line chemotherapy using doxorubicine and ifosfamide. Despite an initial good response, she died with metastatic disease 26 months after diagnosis. We present a rare case of primary temporal bone angiosarcoma and report our experience with a multimode therapeutic approach combining surgery, radiotherapy and chemotherapy.Peer reviewe

Synergistic Anti-Tumor Effects of Combination of Photodynamic Therapy and Arsenic Compound in Cervical Cancer Cells: In Vivo and In Vitro Studies

The effects of As4O6 as adjuvant on photodynamic therapy (PDT) were studied. As4O6 is considered to have anticancer activity via several biological actions, such as free radical production and inhibition of VEGF expression. PDT or As4O6 significantly inhibited TC-1 cell proliferation in a dose-dependent manner (P<0.05) by MTT assay. The anti-proliferative effect of the combination treatment was significantly higher than in TC-1 cells treated with either photodynamic therapy or As4O6 alone (62.4 and 52.5% decrease compared to vehicle-only treated TC-1 cells, respectively, P<0.05). In addition, cell proliferation in combination of photodynamic therapy and As4O6 treatment significantly decreased by 77.4% (P<0.05). Cell survival pathway (Naip1, Tert and Aip1) and p53-dependent pathway (Bax, p21Cip1, Fas, Gadd45, IGFBP-3 and Mdm-2) were markedly increased by combination treatment of photodynamic therapy and As4O6. In addition, the immune response in the NEAT pathway (Ly-12, CD178 and IL-2) was also modulated after combination treatment, suggesting improved antitumor effects by controlling unwanted growth-stimulatory pathways. The combination effect apparently reflected concordance with in vitro data, in restricting tumor growth in vivo and in relation to some common signaling pathways to those observed in vitro. These findings suggest the benefit of combinatory treatment with photodynamic therapy and As4O6 for inhibition of cervical cancer cell growth

Differences in Efficacy and Safety of Pharmaceutical Treatments between Men and Women: An Umbrella Review

Being male or female is an important determinant of risks for certain diseases, patterns of illness and life expectancy. Although differences in risks for and prognoses of several diseases have been well documented, sex-based differences in responses to pharmaceutical treatments and accompanying risks of adverse events are less clear. The objective of this umbrella review was to determine whether clinically relevant differences in efficacy and safety of commonly prescribed medications exist between men and women. We retrieved all available systematic reviews of the Oregon Drug Effectiveness Review Project published before January 2010. Two persons independently reviewed each report to identify relevant studies. We dually abstracted data from the original publications into standardized forms. We synthesized the available evidence for each drug class and rated its quality applying the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Findings, based on 59 studies and data of more than 250,000 patients suggested that for the majority of drugs no substantial differences in efficacy and safety exist between men and women. Some clinically important exceptions, however, were apparent: women experienced substantially lower response rates with newer antiemetics than men (45% vs. 58%; relative risk 1.49, 95% confidence interval 1.35–1.64); men had higher rates of sexual dysfunction than women while on paroxetine for major depressive disorder; women discontinued lovastatin more frequently than men because of adverse events. Overall, for the majority of drugs sex does not appear to be a factor that has to be taken into consideration when choosing a drug treatment. The available body of evidence, however, was limited in quality and quantity, confining the range and certainty of our conclusions

Paclitaxel alters the expression and specific activity of deoxycytidine kinase and cytidine deaminase in non-small cell lung cancer cell lines

<p>Abstract</p> <p>Background</p> <p>We observed that paclitaxel altered the pharmacokinetic properties of gemcitabine in patients with non-small cell lung cancer (NSCLC) and limited the accumulation of gemcitabine and its metabolites in various primary and immortalized human cells. Therefore, we classified the drug-drug interaction and the effects of paclitaxel on deoxycytidine kinase (dCK) and cytidine deaminase (CDA) in three NSCLC cell lines. These enzymes are responsible for the metabolism of gemcitabine to its deaminated metabolite dFdU (80% of the parent drug) and the phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP. These metabolites appear to relate to sensitivity and tolerability of gemcitabine based on previous animal and laboratory studies.</p> <p>Methods</p> <p>Three immortalized human cells representative of the most common histological subtypes identified in patients with advanced NSCLC were exposed to the individual drugs or combinations to complete a multiple drug effect analysis. These same cell lines were exposed to vehicle-control or paclitaxel and the mRNA levels, protein expression and specific activity of dCK and CDA were compared. Comparisons were made using a two-tailed paired t-test or analysis of variance with a P value of < 0.05 considered significant.</p> <p>Results</p> <p>The multiple drug effect analysis indicated synergy for H460, H520 and H838 cells independent of sequence. As anticipated, paclitaxel-gemcitabine increased the number of G2/M cells, whereas gemcitabine-paclitaxel increased the number of G0/G1 or S cells. Paclitaxel significantly decreased dCK and CDA mRNA levels in H460 and H520 cells (40% to 60%, P < 0.05) and lowered dCK protein (24% to 56%, P < 0.05) without affecting CDA protein. However, paclitaxel increased both dCK (10% to 50%) and CDA (75% to 153%) activity (P < 0.05). Paclitaxel caused substantial declines in the accumulation of the deaminated and phosphorylated metabolites in H520 cells (P < 0.05); the metabolites were not measurable in the remaining two cell lines. The ratio of dCK to CDA mRNA levels corresponded to the combination index (CI) estimated for sequential paclitaxel-gemcitabine.</p> <p>Conclusion</p> <p>In summary, paclitaxel altered the mRNA levels and specific activity of dCK and CDA and these effects could be dependent on histological subtype. More cell and animal studies are needed to further characterize the relationship between mRNA levels and the overall drug-drug interaction and the potential to use histological subtype as a predictive factor in the selection of an appropriate anticancer drug regimen.</p

The regional differences in prevalence, medical expenditures and risk factors for injury in Taiwanese teenagers

BACKGROUND: Injury is the leading cause of death in teenagers worldwide. In Taiwan, people in mountainous areas have a 4 to 8 years shorter life span than the general population. Injury among teenagers is likely a major cause. The objective of this study was to investigate the regional differences in the prevalence, the risk factors, and the medical expenditures for injury among Taiwanese teenagers. METHOD: An equal probability national sample was used. In addition, representative samples from mountainous areas and offshore islands were used. Only those who aged between 12 and 21 years, and signed the consent form permitting us to link their National Health Insurance (NHI) claim data were included in the analysis. Injury-related visits and expenditures in outpatient services were extracted from the NHI data. Logistic regression was used to examine the factors associated with injury. For those who had injury related outpatient visits, mixed model was used to examine the factors associated with medical expenditures accounting for multiple visits by the same individual. RESULTS: The prevalence of nonfatal injury was around 30% of teenagers in Taiwan. It was 10% higher in mountainous areas. Factors associated with injury were those who lived in mountainous areas (adjusted odds ratio [OR]: 1.7; 95%; confidence interval [CI]: 1.3–2.3), males (OR: 1.3; 95%; CI: 1.1–1.6), older teens (18–21 years old), and those with risk behavior were positively associated with injury. These factors were also associated with the number of injury-related outpatient visits. However, teenagers in mountainous areas did not spend more on medical care than those who lived in metropolitan Taiwan. CONCLUSION: Around 30% of the teenagers were injured in a year, not including the dead. Each of the injured spent at least 851.4NTD (~27USD) for outpatient visits. The scope of the problem was not trivial. Hazardous environments and high-risk behaviors were the universal causes. In remote areas, lack of medical resources was another possibility. Empowering local people to design prevention programs according to their needs is recommended

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents