Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent microenvironment in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a protective niche. We investigated patients' BM biopsies and found evidence of a similar process in patients receiving induction therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or function. We therefore identified a therapy-induced niche that protects CPCs.

f Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Nevertheless, the molecular mechanism of HBV replication remains elusive. SIRT1 is a class III histone deacetylase that is a structure component of the HBV cccDNA minichromosome. In this study, we found by using microarray-based gene expression profiling analysis that SIRT1 was upregulated in HBV-expressing cells. Gene silencing of SIRT1 significantly inhibited HBV DNA replicative intermediates, 3.5-kb mRNA, and core protein levels. In contrast, the overexpression of SIRT1 augmented HBV replication. Furthermore, SIRT1 enhanced the activity of HBV core promoter by targeting transcription factor AP-1. The c-Jun subunit of AP-1 was bound to the HBV core promoter region, as demonstrated by using a chromatin immunoprecipitation assay. Mutation of AP-1 binding site or knockdown of AP-1 abolished the effect of SIRT1 on HBV replication. Finally, SIRT1 inhibitor sirtinol also suppressed the HBV DNA replicative intermediate, as well as 3.5-kb mRNA. Our study identified a novel host factor, SIRT1, which may facilitate HBV replication in hepatocytes. These data suggest a rationale for the use of SIRT1 inhibitor in the treatment of HBV infection. Hepatitis B virus (HBV) infection remains a major health problem worldwide despite the availability of an effective prevention vaccine. HBV is a hepatotropic, noncytopathic, 3.2-kb partially double-stranded DNA virus (1). Upon viral entry into a hepatocyte, the capsid dissociates, and the genomic relaxed circular DNA (rcDNA) is converted into a covalently closed circular DNA (cccDNA) molecule. The cccDNA is found as a viral minichromosome and acts as the major transcriptional template for the virus. Four major RNA species (3.5-, 2.4-, 2.1-, and 0.7-kb viral RNA transcripts) produced from this viral minichromosome are then transported to and translated in the cytoplasm to produce the viral proteins, namely, viral surface proteins, core protein, viral polymerase, and X protein (2).The control of HBV replication is one of the major strategies to reduce the morbidity and mortality associated with chronic HBV infection. Thus far, no treatment can completely eliminate the infection in all patients with chronic hepatitis B. The chemotherapeutic treatments (i.e., lamivudine, adefovir, entecavir, and telbivudine) inhibit the HBV replication by targeting the viral DNA polymerase. However, long-term treatment leads to the development of problematic drug-resistant virus. Alpha interferon is also useful for treating HBV infection but has substantial side effects. Therefore, identification and characterization of the viral and host factors responsible for HBV infection will provide valuable information for the development of anti-HBV therapeutics.The sirtuin family (SIRT1 to SIRT7) are mammalian homologues of the yeast silent information regulator 2 (Sir2), which are class III histone deacetylases (HDACs) that utilize NAD ϩ as a cofactor for their functions (3). SIRT1, the most wid...

Accumulated data have shown that alternatively activated macrophage exerts a modulatory role in many diseases, including colitis. Interleukin-33 (IL-33), a critical modulator in adaptive and innate immune, has been implicated in autoimmunity and inflammation. Previously, we have reported that IL-33 functions as a protective modulator in TNBS-induced colitis, which is closely related to a Th1-to-Th2/Treg switch. Here, we present novel evidence suggesting that IL-33 primes macrophage into alternatively activated macrophages (AAM) in TNBS-induced colitis. The strong polarized effect of IL-33 was tightly associated with the markedly increased induction of Th2-type cytokines. To confirm the beneficial effects of AAM induced by IL-33, peritoneal AAMs isolated from IL-33-treated mice were transferred to recipient mice with TNBS colitis. The adoptive transfer resulted in prominent inhibition of disease activity and inflammatory cytokines in the TNBS-treated mice. In conclusion, our data provide clear evidence that IL-33 plays a protective role in TNBS-induced colitis, which is closely related to AAM polarization.

TEM-1, mediated by plasmid and transposon, is the most commonly encountered β-lactamase in Gram-negative bacteria. Four different promoters upstream of bla TEM -related genes have been identified: the weak P3 promoter, and the strong promoters Pa/Pb , P4 , and P5. In this study, we investigated the genetic basis of a clinical strain of Escherichia coli (RJ904), which was found to be resistant to BLBLIs (β-lactam/β-lactamase inhibitors), including amoxicillin-clavulanate, ticarcillin-clavulanate (TCC), and piperacillin-tazobactam (TZP) but sensitive to third-generation cephalosporins. The conjugation test and S1-nuclease pulsed-field gel electrophoresis (S1-PFGE) demonstrated that transfer of this resistance was mediated by a ca. 100 kb plasmid. The transformant with TZP resistance was screened out with the shortgun cloning. Sequence analysis revealed that the recombinant plasmid contained a bla TEM-1b gene with the strong promoter Pa/Pb . Different plasmids were cloned based on the clone vector pACYC184 with the insertion of the bla TEM-1b gene with promoters Pa/Pb or P3 . Susceptibility to TZP was determined by the E -test, agar dilution, and broth microdilution. The level of bla TEM-1b -specific transcription was determined by quantitative real-time PCR. Substitution of Pa/Pb for P3 resulted in a 128-fold decline of the MIC value of TZP, from >1024 mg/L to 8 mg/L, and a significantly lower bla TEM-1b expression level. Hyperproduction of TEM-1 β-lactamase mediated by the promoter Pa/Pb was responsible for high resistance to TZP in E. coli . Our data show possible risks of resistance development in association with the clinical use of TZP. The bla TEM promoter modifications should be considered for whole genome whole-genome sequencing-inferred bacterial antimicrobial susceptibility testing.