Clinical Outcome among Nasopharyngeal Cancer Patients in a Multi-Ethnic Society in Singapore

BackgroundNasopharyngeal cancer (NPC) is endemic among Chinese populations in Southeast Asia. However, the outcomes of non-Chinese NPC patients in Singapore are not well reported.AimTo determine if non-Chinese NPC patients have a different prognosis and examine the clinical outcomes of NPC patients in a multi-ethnic society.MethodsRetrospective chart review of 558 NPC patients treated at a single academic tertiary hospital from 2002 to 2012. Survival and recurrence rates were analysed and predictive factors identified using the Kaplan-Meier method and Cox regression model.ResultsOur cohort comprised 409 males (73.3%) and 149 females (26.7%) with a median age of 52 years. There were 476 Chinese (85.3%), 57 Malays (10.2%), and 25 of other ethnic groups (4.5%). Non-Chinese patients were more likely to be associated with advanced nodal disease at initial presentation (p = 0.049), compared with the Chinese. However, there were no statistical differences in their overall survival (OS) or disease specific survival (DSS) (p = 0.934 and p = 0.857 respectively). The 3-year and 5-year cohort OS and DSS rates were 79.3%, 70.7%, and 83.2%, 77.4% respectively. Advanced age (p<0.001), N2 disease (p = 0.036), N3 disease (p<0.001), and metastatic disease (p<0.001) at presentation were independently associated with poor overall survival. N2 disease (p = 0.032), N3 disease (p<0.001) and metastatic disease (p<0.001) were also independently associated with poor DSS. No predictive factors were associated with loco-regional recurrence after definitive treatment. Advanced age (p = 0.044), N2 disease (p = 0.033) and N3 disease (p<0.001) were independently associated with distant relapse.ConclusionIn a multi-ethnic society in Singapore, non-Chinese are more likely to present with advanced nodal disease. This however did not translate into poorer survival outcomes. Older patients with N2 or N3 disease are associated with a higher risk of distant relapse and poor overall survival.     

Inflammatory and Repair Pathways Induced in Human Bronchoalveolar Lavage Cells with Ozone Inhalation

Background

Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury.

Methods

To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay].

Results

Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9β1 integrin-dependent manner.

Conclusions

Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury.     

Participation in Complex and Social Everyday Activities Six Years after Stroke: Predictors for Return to Pre-Stroke Level

Background

Long-term disability following stroke can lead to participation restrictions in complex and social everyday activities, yet information is lacking on to what extent stroke survivors return to their pre-stroke levels of participation.

Objectives

The objectives of this study were to investigate the level of participation in complex and social everyday activities 6 years after stroke, to compare this with pre-stroke participation and to identify predictors of returning to pre-stroke levels of participation.

Method

All patients admitted to Karolinska University Hospital''s stroke units during a 1-year period were eligible to participate and 349 patients were recruited. Assessments were made at base-line, 3 months and 6 years using self-reported outcome measures. Participation was assessed using the Frenchay Activities Index (FAI). The 6-year score for each participant was compared to the pre-stroke score, both for the total score and for each domain (domestic chores, leisure/work and outdoor activities). Predictors of having the same or better level of participation at 6 years were identified using logistic regression.

Results

At 6 years, 121 participants were followed up, 166 were deceased, 44 declined to take part and 18 could not be traced. At 6 years 84% could be described as active (FAI≥15). The same level of participation or better than pre-stroke was found in 35% of participants, in 65% the level was lower. Similar predictors were identified for achieving the same or better level of participation at 6 years for FAI total and the three domains; ability to walk without aids and a lower age at stroke onset, and perceived mobility, participation and recovery at 3 months.

Conclusion

Six years after stroke, 35% of participants had the same or better level of participation as pre-stroke. Rehabilitation after stroke to improve walking ability and participation might improve long-term participation in complex and social everyday activities.     

Erythrocyte and reticulocyte binding-like proteins of Plasmodium falciparum

The global agenda for malaria eradication would benefit from development of a highly efficacious vaccine that protects against disease and interrupts transmission of Plasmodium falciparum. It is likely that such a vaccine will be multi-component, with antigens from different stages of the parasite life cycle. In this review, inclusion of blood stage antigens in such a vaccine is discussed. Erythrocyte binding-like (EBL) and P. falciparum reticulocyte binding-like (PfRh) proteins are reviewed with respect to their function in erythrocyte invasion, their role in eliciting antibodies contributing to protective immunity and reduction of invasion, leading subsequently to inhibition of parasite multiplication.     

Septins Regulate Bacterial Entry into Host Cells

Background

Septins are conserved GTPases that form filaments and are required in many organisms for several processes including cytokinesis. We previously identified SEPT9 associated with phagosomes containing latex beads coated with the Listeria surface protein InlB.

Methodology/Principal Findings

Here, we investigated septin function during entry of invasive bacteria in non-phagocytic mammalian cells. We found that SEPT9, and its interacting partners SEPT2 and SEPT11, are recruited as collars next to actin at the site of entry of Listeria and Shigella. SEPT2-depletion by siRNA decreased bacterial invasion, suggesting that septins have roles during particle entry. Incubating cells with InlB-coated beads confirmed an essential role for SEPT2. Moreover, SEPT2-depletion impaired InlB-mediated stimulation of Met-dependent signaling as shown by FRET.

Conclusions/Significance

Together these findings highlight novel roles for SEPT2, and distinguish the roles of septin and actin in bacterial entry.     

Multiple-locus variable-number tandem-repeats analysis of Listeria monocytogenes using multicolour capillary electrophoresis and comparison with pulsed-field gel electrophoresis typing

The multiple-locus variable-number tandem-repeats analysis (MLVA) method for genotyping has proven to be a fast and reliable typing tool in several bacterial species. MLVA is in our laboratory the routine typing method for Salmonella enterica subsp. enterica serovar Typhimurium and Escherichia coli O157. The gram-positive bacteria Listeria monocytogenes, while not isolated as frequent as S. Typhimurium and E. coli, causes severe illness with an overall mortality rate of 30%. Thus, it is important that any outbreak of this pathogen is detected early and a fast trace to the source can be performed. In view of this, we have used the information provided by two fully sequenced L. monocytogenes strains to develop a MLVA assay coupled with high-resolution capillary electrophoresis and compared it to pulsed-field gel electrophoresis (PFGE) in two sets of isolates, one Norwegian (79 isolates) and one Swedish (61 isolates) set. The MLVA assay could resolve all of the L. monocytogenes serotypes tested, and was slightly more discriminatory than PFGE for the Norwegian isolates (28 MLVA profiles and 24 PFGE profiles) and opposite for the Swedish isolates (42 MLVA profiles and 43 PFGE profiles).     

Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.     

Dynamics of CCR5 expression by CD4(+) T cells in lymphoid tissues during simian immunodeficiency virus infection

Early viral replication and profound CD4(+) T-cell depletion occur preferentially in intestinal tissues of macaques infected with simian immunodeficiency virus (SIV). Here we show that a much higher percentage of CD4(+) T cells in the intestine express CCR5 compared with those found in the peripheral blood, spleen, or lymph nodes. In addition, the selectivity and extent of the CD4(+) T-cell loss in SIV infection may depend upon these cells coexpressing CCR5 and having a "memory" phenotype (CD45RA(-)). Following intravenous infection with SIVmac251, memory CD4(+) CCR5(+) T cells were selectively eliminated within 14 days in all major lymphoid tissues (intestine, spleen, and lymph nodes). However, the effect on CD4(+) T-cell numbers was most profound in the intestine, where cells of this phenotype predominate. The CD4(+) T cells that remain after 14 days of infection lacked CCR5 and/or were naive (CD45RA(+)). Furthermore, when animals in the terminal stages of SIV infection (with AIDS) were examined, virtually no CCR5-expressing CD4(+) T cells were found in lymphoid tissues, and all of the remaining CD4(+) T cells were naive and coexpressed CXCR4. These findings suggest that chemokine receptor usage determines which cells are targeted for SIV infection and elimination in vivo.