Clinical Studies

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Last updated: 13th August 2010

Clinical Studies
Gastric Cancer-Specific Protein Profile Identified Using Endoscopic Biopsy Samples via MALDI Mass Spectrometry.
J Proteome Res. 2010 Aug 6;9(8):4123-30.
To date, proteomic analyses on gastrointestinal cancer tissue samples have been performed using surgical specimens only, which are obtained after a diagnosis is made. To determine if a proteomic signature obtained from endoscopic biopsy samples could be found to assist with diagnosis, frozen endoscopic biopsy samples collected from 63 gastric cancer patients and 43 healthy volunteers were analyzed using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. A statistical classification model was developed to distinguish tumor from normal tissues using half the samples and validated with the other half. A protein profile was discovered consisting of 73 signals that could classify 32 cancer and 22 normal samples in the validation set with high predictive values (positive and negative predictive values for cancer, 96.8% and 91.3%; sensitivity, 93.8%; specificity, 95.5%). Signals overexpressed in tumors were identified as alpha-defensin-1, alpha-defensin-2, calgranulin A, and calgranulin B. A protein profile was also found to distinguish pathologic stage Ia (pT1N0M0) samples (n = 10) from more advanced stage (Ib or higher) tumors (n = 48). Thus, protein profiles obtained from endoscopic biopsy samples may be useful in assisting with the diagnosis of gastric cancer and, possibly, in identifying early stage disease.

HIV-1 exposed uninfected men who have sex with men have increased levels of salivary CC-chemokines associated with sexual behavior.
AIDS. 2010 Jun 19;24(10):1569-75.
OBJECTIVES: To determine whether soluble molecules with known anti-HIV-1 activity are increased in saliva of HIV-1 exposed uninfected individuals of discordant couples of men who have sex with men (MSM), and whether the levels of these molecules are associated with genetic polymorphisms, sexual behavior and/or HIV-1 neutralizing capacity. METHODS: Saliva and PBMC were collected from exposed uninfected individuals (n=25), and low-risk controls (n=22). Levels of CCL2, CCL3, CCL4, CCL5 and CCL11 were detected by Luminex, and SLPI, LL-37, alpha-defensins and IgA2 were detected by ELISA. Single nucleotide polymorphisms (SNPs) were investigated using mass spectrometry or PCR-sequencing. HIV-1 neutralizing activity was assessed using PBMCbased neutralization assays. Self-reported questionnaires described sexual behavior. RESULTS: Exposed uninfected individuals had significantly higher levels of salivary CCL2, CCL4, CCL5 and CCL11 as compared with controls although genetic polymorphisms within the corresponding regions were equally distributed. IgA2 was also increased in exposed uninfected individuals, whereas neither CCL3, SLPI, LL-37 nor alpha-defensins differed between exposed uninfected individuals and controls. The HIV-1 neutralizing capacity of saliva was associated with higher levels of CC-chemokines (but not SLPI, LL-37, alpha-defensins or IgA2) in both exposed uninfected individuals and controls. The increased levels of CC-chemokines were associated with a higher frequency of unprotected oral sex and/or additional casual sex partners. CONCLUSION: HIV-1 exposed uninfected MSM had higher levels of salivary CC-chemokines compared with controls, this finding associated with sexual behavior rather than with genetic polymorphisms. The increased levels of CC-chemokines associated with HIV-1 neutralizing capacity in saliva.

History of eczema herpeticum is associated with the inability to induce human beta-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis.
Br J Dermatol. 2010 Jun 9. [Epub ahead of print]

Tumor necrosis factor and norepinephrine lower the levels of human neutrophil peptides 1-3 secretion by mixed synovial tissue cultures in osteoarthritis and rheumatoid arthritis.
Arthritis Res Ther. 2010 Jun 4;12(3):R110.
INTRODUCTION: Neutrophils and monocytes play an important role in overt inflammation in chronic inflammatory joint diseases such as rheumatoid arthritis (RA). The sympathetic nervous system (SNS) inhibits many neutrophil / monocyte functions and macrophage tumor necrosis factor (TNF), but due to the loss of sympathetic nerve fibers in inflamed tissue, sympathetic control is attenuated. In this study, we focused on noradrenergic and TNF regulation of human neutrophil peptides 1-3 (HNP1-3), which are proinflammatory bactericidal alpha defensins. METHODS: Synovial tissue and cells were obtained from patients with RA and osteoarthritis (OA). Using immunohistochemistry and immunofluorescence, HNP1-3 were tracked in the tissue. With synovial cell culture experiments and ELISA, effects of norepinephrine, TNF, and cortisol on HNP1-3 were detected. RESULTS: HNP1-3 were abundantly expressed in the synovial lining and adjacent sublining area but not in deeper layers of synovial tissue. The human beta-defensin-2, used as control, was hardly detectable in the tissue and in supernatants. HNP1-3 double-stained with neutrophils but not with macrophages, fibroblasts, T/B lymphocytes, and mast cells. Norepinephrine dose-dependently decreased HNP1-3 levels from RA and OA cells. TNF also inhibited HNP1-3 levels from OA but not from RA cells. Cortisol inhibited HNP1-3 levels only in OA patients. A combination of norepinephrine and cortisol did not show additive or synergistic effects. CONCLUSIONS: This study demonstrated an inhibitory effect of norepinephrine on HNP1-3 of mixed synovial cells. In light of these findings, the loss of sympathetic nerve fibers with low resting norepinephrine levels might also augment the inflammatory process via HNP1-3.

Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population.
Anesthesiology. 2010 Jun;112(6):1428-34.
BACKGROUND: Human neutrophil peptides 1-3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1-3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. METHODS: This case-control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were detected. RESULTS: The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 x 10, odds ratio 2.77, 95% confidence interval 1.85-4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 x 10, odds ratio 2.66, 95% confidence interval 1.69-4.19). This established association was replicated in a second age- and gender-matched case-control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11-3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). CONCLUSIONS: DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.

Analysis of beta-defensin and Toll-like receptor gene copy number variation in Celiac disease.
Hum Immunol. 2010 Aug;71(8):833-836.
Celiac disease (CD) is an immune-mediated disorder of the gut in which innate and adaptive responses are involved. Toll-like Receptor (TLR) 2 and TLR4 participate in host defense through antigen recognition, and show altered expression in CD gut mucosa. Beta-defensins are inducible antimicrobial peptides and DEFB gene copy number polymorphisms have been associated with autoimmune and inflammatory disorders. We performed copy number analysis of TLR2, TLR4 and the beta-defensin cluster (DEFB4, DEFB103 and DEFB104) by gene-specific real-time PCR in 376 CD patients and 376 controls. TLR genes did not show copy number variation and all samples presented 2 copies. Beta-defensin cluster varied between 2 and 9 copies per genome, and when grouped into bins, high copy numbers (>4) were underrepresented among patients [p=0.023; OR=0.69 (95% CI: 0.50-0.96)] suggesting that increased copy numbers could protect from CD, possibly by impeding bacterial infiltration more efficiently and preserving gut epithelial integrity.

[HBD-1 and hBD-2 are expressed in cervico-vaginal lavage in female genital tract due to microbial infections]
Ginekol Pol. 2010 Apr;81(4):268-71.
OBJECTIVES: The aim of this study was to evaluate and compare concentration of selected human beta-defensins (hBD-1, hBD-2) in cervico-vaginal lavage (CVL), obtained from women with candidiasis, chlamydiasis and other bacterial infections. MATERIAL AND METHODS: beta-defensins were detected quantitatively by RT-PCR (7000 Taqman, Applied Biosystems) in cervico-vaginal lavage collected from 120 (79 women in the study group and 41 controls) non-pregnant women, aged 18-40 (mean age 28.5 +/- 6.29). The study group patients were divided into three subgroups on the basis of clinical and microbiological diagnosis: women with candidiasis (n=13); with chlamydiasis (n=13), and with other bacterial infections (n=12). RESULTS: The highest count of hBD-1 RNA copies was found in women with bacterial infections and candidiasis (335.84 and 320.10 respectively), and hBD-2--with chlamydiasis. The difference between RNA copies of hBD-1/microg in candidiasis, chlamydiasis and bacterial pathogens was statistically significant; for hBD-2 only in case of chlamydiasis. CONCLUSIONS: Chlamydia trachomatis infection activates the production of hBD-2. Candida albicans, Chlamydia trachomatis, and bacterial pathogens induced variable increases of hBD-1 concentration.

Beta2-agonists promote host defense against bacterial infection in primary human bronchial epithelial cells.
BMC Pulm Med. 2010 May 14;10(1):30.
ABSTRACT: BACKGROUND: Airway epithelial cells are critical in host defense against bacteria including Mycoplamsa pneumoniae (Mp) in chronic obstructive pulmonary disease (COPD) and asthma. beta2-agonists are mainstay of COPD and asthma therapy, but whether beta2-agonists directly affect airway epithelial host defense functions is unclear. METHODS: Epithelial cells from bronchial brushings of normal (n = 8), asthma (n = 8) and COPD (n = 8) subjects were grown in air-liquid interface cultures, and treated with cigarette smoke extract (CSE) and/or Th2 cytokine IL-13, followed by Mp infection and treatment with beta2-agonists albuterol and formoterol for up to seven days. Mp and host defense proteins short palate, lung, and nasal epithelial clone 1 (SPLUNC1) and beta-defensin-2 were quantified. Expression of beta2-adrenergic receptors was also measured by real-time quantitative RT-PCR. RESULTS: (R)- or racemic albuterol and (R,R)- or racemic formoterol significantly decreased Mp levels in normal and asthma epithelial cells. Normal cells treated with Mp and (R)- or racemic albuterol showed an increase in SPLUNC1, but not in beta-defensin-2. COPD cells did not respond to drug treatment with a significant decrease in Mp or an increase in SPLUNC1. IL-13 attenuated drug effects on Mp, and markedly decreased SPLUNC1 and beta2-adrenergic receptors. CONCLUSIONS: These results for the first time show that beta2-agonists enhance host defense functions of primary bronchial epithelial cells from normal and asthma subjects, which is attenuated by IL-13.

Correlation of levels of alpha-defensins determined by HPLC-ESI-MS in bronchoalveolar lavage fluid with the diagnosis of pneumonia in premature neonates.
Pediatr Res. 2010 Aug;68(2):140-4.
The presence of alpha-defensins in bronchoalveolar lavage fluid (BALF) was investigated in a cohort of preterm newborns with gestational age (GA)
Influence of gestational age, cesarean section, and type of feeding on fecal human beta-defensin 2 and tumor necrosis factor-alpha.
J Pediatr Gastroenterol Nutr. 2010 Jul;51(1):103-5.
OBJECTIVE:: Development of the mucosal immune system is essential for controlling antigenic response. External factors are known to influence the immune system, such as breast-feeding or the mode of delivery. The aim of the present study was to investigate maturation of the enteric immune system. PATIENTS AND METHODS:: In stool samples of 59 preterm and term-born infants we measured the concentration of human beta-defensin 2 (HBD 2), an endogenous antimicrobial peptide, and tumor necrosis factor-alpha (TNF-alpha), a cytokine playing a central role in mucosal inflammation, by enzyme-linked immunosorbent assay. RESULTS:: Mode of delivery as well as nutrition (breast-feeding or formula) had no influence on the fecal concentration of HBD-2 or TNF-alpha, but there was a significant increase in the concentration of HBD-2 in correlation with gestational age. TNF-alpha showed no change in concentration. CONCLUSIONS:: Low fecal HBD-2 may be a risk factor in preterm infants to develop neonatal enteric disease, such as necrotizing enterocolitis.