Although the pathogenic and genetic basis of acute lung injury (ALI) remains incompletely understood, the identification of novel ALI biomarkers holds promise for unique insights. Expression profiling in animal models of ALI (canine and murine) and human ALI detected significant expression of pre-B-cell colony-enhancing factor (PBEF), a gene not previously associated with lung pathophysiology. These results were validated by real-time polymerase chain reaction and immunohistochemistry studies, with PBEF protein levels significantly increased in both bronchoalveolar lavage fluid and serum of ALI models and in cytokine- or cyclic stretch-activated lung microvascular endothelium. We genotyped two PBEF single-nucleotide polymorphisms (SNPs) in a well characterized sample of white patients with sepsis-associated ALI, patients with severe sepsis, and healthy subjects and observed that carriers of the haplotype GC from SNPs T-1001G and C-1543T had a 7.7-fold higher risk of ALI (95% confidence interval 3.01-19.75, p < 0.001). The T variant from the SNP C-1543T resulted in a significant decrease in the transcription rate (1.8-fold; p < 0.01) by the reporter gene assay. Together, these results strongly indicate that PBEF is a potential novel biomarker in ALI and demonstrate the successful application of robust genomic technologies in the identification of candidate genes in complex lung disease.

Rationale: Polymorphisms affecting Toll-like receptor (TLR)-mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis. Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis. Methods: We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case-control study in a cohort of intensive care unit patients with sepsis, and a case-control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects. Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1 27202A/G (rs5743551), which associated with elevated TLR1-mediated cytokine production (P , 2 3 10 220 ). TLR1 27202G marked a coding SNP that causes higher TLR1-induced NF-kB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1 27202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR1 27202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR1 27202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and grampositive infection in sepsis.

IntroductionThe Isodon plant, Rabdosia rubescens (RR), and its extracts, were shown in China to be able to suppress disease progress, reduce tumor burden, alleviate syndrome, and prolong survival in patients with esophageal, gastric carcinoma or liver cancer. [1][2][3][4][5] Of interest, other Isodon plants including Isodon japonicus Hara (IJ) and I trichocarpus (IT) were also applied as home remedies for similar disorders in Japan and Korea. 6 Oridonin ( Figure 1A), a bitter tetracycline diterpenoid compound, was isolated from RR, IJ, and IT separately, 7,8 suggesting oridonin should be an essential antitumor component of Isodon plants. Studies showed that oridonin induced apoptosis in a variety of cancer cells including those from prostate, breast, non-small cell lung cancers, acute leukemia (NB4, HL-60 cells), glioblastoma multiforme, and human melanoma cells. [9][10][11][12] Oridonin could also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia. 13,14 However, though studies showed that caspase-3 (casp-3), casp-8, P53, Bcl-2/Bax, cytochrome c (cyt C), 10,15,16 and nuclear factor kappa B (NFB) 17 were involved in apoptosis induced by oridonin, mechanisms underlying the antitumor activity of oridonin remain largely unknown, and whether oridonin can find clinical application still needs more investigation.Genetic abnormalities have been shown to play a key role in leukemogenesis, 18 and treatment strategies interfering with oncoproteins involved in leukemia pathogenesis have been reported to have high therapeutic efficacy with low adverse effects. The BCR-ABL-targeting STI-571, in the treatment of chronic myeloid leukemia (CML), 19 and the PML-RAR␣-targeting agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), in taming acute promyelocytic leukemia (APL), 20,21 can serve as paradigms. Hence molecular target-based therapies should be developed for leukemias with poor prognosis. The AML1-ETO (AE) fusion gene is the result of translocation t(8;21)(q22;q22), which is seen in 40% to 80% of M2-type acute myeloid leukemia (AML M2) and 12% to 20% of all cases of AML. 22,23 The AE fusion protein recruits the nuclear receptor corepressor (NCoR)-mammalian Sin3 (mSin3)-histone deacetylase (HDAC) complex, 24,25 inhibits transcription of AML1 target genes 22,24 including interleukin-3 (IL3), 26 activates transcription of apoptotic antagonist Bcl-2, 27 up-regulates protein tyrosine kinase C-KIT, 28 induces the expression of granulocyte colony-stimulating factor receptor (G-CSFR) as well as myeloperoxidase (MPO), 29 and blocks transactivation of the GM-CSF promoter. 30 The AE oncoprotein enhances self-renewal of hematopoietic stem/progenitor cells, blocks hematopoietic differentiation, disturbs normal cell proliferation, 31 and immortalizes murine hematopoietic progenitors. 32,33 Although reports suggest that additional mutations are required to cooperate with AE to cause murine The online version of this article contains a data supplement.The publication costs of this article were defr...