Sepsis results from the host hyperinflammatory response to bacterial infection, causing multiple organ failure and high mortality. We previously demonstrated that LPS binds to monocytic membrane-bound thrombomodulin (TM), but the role of monocytic TM in LPS-induced inflammation remains unknown. In this study, we demonstrated that TM knockdown in human monocytic cells attenuated LPS-induced signaling pathways and cytokine production. Coimmunoprecipitation and immunofluorescence assays showed that monocytic TM interacted with the LPS receptors, CD14 and TLR4/myeloid differentiation factor-2 (MD-2) complex, indicating that it binds to LPS and triggers an LPS-induced inflammatory response by interacting with the CD14/TLR4/MD-2 complex. We also found that monocytic TM knockdown reduced cytokine production induced by Gram-negative bacteria Klebsiella pneumoniae, suggesting that monocytic TM plays an important role in Gram-negative bacteria-induced inflammation. To further investigate the function of monocytic TM in vivo, myeloid-specific TM-deficient mice were established and were found to display improved survival that resulted from the attenuation of septic syndrome, including reduced systemic inflammatory response and resistance to bacterial dissemination, after K. pneumoniae infection or cecal ligation and puncture surgery. The inhibition of bacterial dissemination in mice with a deficiency of myeloid TM may be caused by the early increase in neutrophil infiltration. Therefore, we conclude that monocytic TM is a novel component in the CD14/TLR4/MD-2 complex and participates in the LPS- and Gram-negative bacteria-induced inflammatory response.

Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer, but little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site-specific cancer in a large, regionally diverse cohort (450,934 white, non-Hispanic subjects (50-71 years old) in the prospective NIH-AARP Diet and Health Study) after accounting for individual-level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the U.S. Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HR) and 95% confidence intervals (CI) for quartiles of UVR exposure. Restricted cubic splines examined non-linear relationships. Over 9 years of follow-up, UVR exposure was inversely associated with total cancer risk (N=75,917; highest vs. lowest quartile, HR=0.97 (0.95, 0.99), p-trend<0.001). In site-specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest vs. lowest quartile, HR=1.22 (1.13, 1.32), p-trend<0.001) and decreased risk of Non-Hodgkin's lymphoma (HR=0.82 (0.74, 0.92)) and colon (HR=0.88 (0.82, 0.96)), squamous cell lung (HR=0.86 (0.75, 0.98)), pleural (HR=0.57 (0.38, 0.84)), prostate (HR=0.91 (0.88, 0.95)), kidney (HR=0.83 (0.73, 0.94)), and bladder (HR=0.88 (0.81, 0.96)) cancers (all p-trend<0.05). We also found non-linear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer.

The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver but has no known physiological functions. Here we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin(-/-)) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and anti-hepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin(-/-) mouse liver as a result of retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective pro-hepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin(-/-) mice. Treatment of hepsin(-/-) mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes seen in hepsin(-/-) mice. Conclusion: Our findings show that maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin-mediated changes in liver architecture significantly enhance tumor metastasis to the liver.(HEPATOLOGY 2012.).

Homologous recombination (HR) represents a major error-free pathway to eliminate pre-carcinogenic chromosomal lesions. The DNA strand invasion reaction in HR is mediated by a helical filament of the Rad51 recombinase assembled on single-stranded DNA that is derived from the nucleolytic processing of the primary lesion. Recent studies have found that the human and mouse Swi5 and Sfr1 proteins form a complex that influences Rad51-mediated HR in cells. Here, we provide biophysical evidence that the mouse Swi5-Sfr1 complex has a 1:1 stoichiometry. Importantly, the Swi5-Sfr1 complex, but neither Swi5 nor Sfr1 alone, physically interacts with Rad51 and stimulates Rad51-mediated homologous DNA pairing. This stimulatory effect stems from the stabilization of the Rad51-ssDNA presynaptic filament. Moreover, we provide evidence that the RSfp (rodent Sfr1 proline rich) motif in Sfr1 serves as a negative regulatory element. These results thus reveal an evolutionarily conserved function in the Swi5-Sfr1 complex and furnish valuable information as to the regulatory role of the RSfp motif that is specific to the mammalian Sfr1 orthologs.

Using a mouse model we show that self-complementary (sc) adeno-associated virus (AAV) vectors pseudotyped with capsids of serotypes 2, 7 or 8 induce more potent transgene product-specific CD8(+) T cell and antibody responses compared to corresponding single-stranded (ss)AAV vectors. These data suggest that the higher and more rapidly appearing amounts of transgene product achieved with scAAV vectors may increase detrimental immune responses in gene transfer recipients.

BACKGROUND: The absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T-cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T-cell ALL. PROCEDURE: Forty-five children with T-cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q-PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q-PCR was defined as a fold-change <0.35. RESULTS: ABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23-53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10-16.42). CONCLUSIONS: The absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T-cell ALL in Taiwan. Providing patients with T-cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials. Pediatr Blood Cancer © 2011 Wiley Periodicals, Inc.

Progesterone (P4) and estradiol (E2) modulate neurogenesis and synaptic remodeling in the hippocampus during the rat estrous cycle and in response to deafferenting lesions, but little is known about the steroidal regulation of hippocampal progesterone receptors associated with these processes. We examined the neuronal expression of progesterone receptor membrane component-1 (Pgrmc1) and the classical progesterone receptor (Pgr), by in situ hybridization and immunohistochemistry. Pgr, a transcription factor, has been associated with synaptic remodeling and other major actions of P4, whereas Pgrmc1 is implicated in P4-dependent proliferation of adult neuroprogenitor cells and with rapid P4 effects on membranes. Ovariectomized adult rats were given E2, P4, or E2+P4 on two schedules: a 4-d model of the rodent estrous cycle and a 30-d model of postmenopausal hormone therapy. Pgr was hormonally responsive only in CA1 pyramidal neurons, and the induction of Pgr by E2 was partly antagonized by P4 only on the 30-d schedule. In CA3 pyramidal and dentate gyrus (DG) neurons, Pgr was largely unresponsive to all hormone treatments. In contrast to Pgr, Pgrmc1 was generally induced by E2 and/or P4 throughout the hippocampus in CA1, CA3, and DG neurons. In neuroprogenitor cells of the DG (immunopositive for bromodeoxyuridine and doublecortin), both Pgrmc1 and Pgr were detected. The differential regulation of hippocampal Pgrmc1 and Pgr by E2 and P4 may guide drug development in hormonal therapy for support of neurogenesis and synaptic regeneration.

OBJECTIVES: Dengue virus (DENV) infection may result in severe dengue hemorrhage fever (DHF). However the mechanisms to cause hemorrhage during DENV infection are not fully understood. The sera level of secreted DENV nonstructural protein 1 (NS1) is correlated with the development of DHF. However, whether secreted NS1 can interfere with coagulation and contribute to the hemorrhage in DHF is unknown. Since thrombin plays a very important role in the activation of coagulation, we investigated whether NS1 can bind to thrombin and affect its formation or activity. METHODS AND RESULTS: We first demonstrated that NS1 could bind to thrombin and formed NS1/thrombin complex in dengue patients' sera by enzyme-linked immunosorbent assay (ELISA). The ability of NS1 binding to prothrombin or thrombin was further confirmed using recombinant NS1 (rNS1) by ELISA, co-immunoprecipitation, and rNS1-affinity column purification. Even though the binding of rNS1 to thrombin showed no effect on thrombin activity, rNS1 could inhibit prothrombin activation and prolong activated partial thromboplastin time (APTT) of human platelet poor plasma. CONCLUSION: These results suggest secreted DENV NS1 may bind to prothrombin and inhibit it activation, which in turn, may contribute to the APTT prolongation and hemorrhage in DHF patients.

BACKGROUND Rhinitis and sinusitis are very common medical conditions and have been shown to be frequently associated. The role of allergies in the pathogenesis of chronic rhinosinusitis has been confirmed; however, the role of allergies in acute rhinosinusitis is debatable. Nonetheless, allergies are an important factor in the development of rhinosinusitis. OBJECTIVE To evaluate the incidence of allergic rhinitis in patients with acute rhinosinusitis and identify the clinical spectrum in Taiwan. METHODS This study randomly recruited 69 participants between 3 and 12 years of age with acute rhinosinusitis over the period of one and a half years. All participants underwent a nasal peak expiratory flow rate (nPEFR) test, skin-Prick test (SPT), nasal smear examination, nasal culture, radiography (Water's projection) and were requested to complete the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) as well as provide their allergic history. RESULTS Among the 69 participants in the study, 27 (39.1%) participants were shown to have allergic rhinitis. The most troublesome symptoms among the 69 participants with acute rhinosinusitis were postnasal drip (3.00 ± 1.29), nasal obstruction (2.94 ± 1.39) and cough (2.67 ± 1.42). The most troublesome symptoms among the 27 participants with acute rhinosinusitis combined with allergic rhinitis were nasal obstruction (3.33 ± 1.24), postnasal drip (3.22 ± 1.09) and itchy eyes (2.74 ± 1.43) and with the higher values. In addition, the participants (≧ 6 y/o) with acute rhinosinusitis combined with allergic rhinitis had significantly lower nPEFR values compared with the nonatopic children (75.2 ± 18.2 vs 96.6 ± 21.4, p<0.05). If nPEFR is below 75 mL/min, the positive predict value in the patients of acute rhinosinusitis is 75.0% combined with allergic rhinitis (sensitivity 63.2%; specificity 85.7%). Streptococcus pneumoniae (29.0%), Haemophilus influenzae (20.3%), and Moraxella catarrhalis (17.4%) were the major isolated pathogens in this study. The prevalence of colonization with Staphylococcus aureus in the 69 participants with acute rhinosinusitis was 23.2%, and 15.9% for methicillin-resistant S. aureus (MRSA). CONCLUSION This study demonstrated that the bacteriological properties of acute rhinosinusitis among children in Taiwan are the same as those in other parts of the world; however, the prevalence of colonization by MRSA was higher than among healthy children. Second, atopic children were more likely to develop acute rhinosinusitis than nonatopic children. Third, most Taiwanese children with acute rhinosinusitis complained of postnasal drip, nasal obstruction and cough. If a child suffering from acute rhinosinusitis complained of severe nasal obstruction (nPEFR≦75 mL/min), the doctor should be alerted to atopic conditions requiring further treatment. The issues dealt with in this study may require further research with a larger sample population over an extended period of time to verify these conclusions.