Summary Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV2. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain3–7, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit8. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy.

Macrophages from C57BL/6J (B6) mice restrict growth of the intracellular bacterial pathogen Legionella pneumophila. Restriction of bacterial growth requires caspase-1 and the leucine-rich repeat-containing protein Naip5 (Birc1e). We identified mutants of L. pneumophila that evade macrophage innate immunity. All mutants were deficient in expression of flagellin, the primary flagellar subunit, and failed to induce caspase-1-mediated macrophage death. Interestingly, a previously isolated flagellar mutant (fliI) that expresses, but does not assemble, flagellin did not replicate in macrophages, and induced macrophage death. Thus, flagellin itself, not flagella or motility, is required to initiate macrophage innate immunity. Immunity to Legionella did not require MyD88, an essential adaptor for toll-like receptor 5 (TLR5) signaling. Moreover, flagellin of Legionella and Salmonella induced cytotoxicity when delivered to the macrophage cytosol using Escherichia coli as a heterologous host. It thus appears that macrophages sense cytosolic flagellin via a TLR5-independent pathway that leads to rapid caspase-1-dependent cell death and provides defense against intracellular bacterial pathogens.

IntroductionGastric cancer is a fatal malignancy with a rising incidence rate. Effective methods for early diagnosis, monitoring metastasis, and prognosis are currently unavailable for gastric cancer. In this study, we examined the association of programmed death ligand-1 (PD-L1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with the prognosis of gastric cancer.MethodsThe expressions of PD-L1 and APE1 were detected by immunohistochemistry in 107 cases of human gastric carcinoma. The correlation of PD-L1 and APE1 expression with the clinicopathologic features of gastric carcinoma was analyzed by SPSS version 19.0.ResultsThe positive expression rates of PD-L1 and APE1 in gastric cancer tissues were 50.5% (54/107) and 86.9% (93/107), respectively. PD-L1 and APE1 positive expressions were significantly associated with depth of invasion, lymph node metastasis, pathological type, overall survival, and higher T stage. Furthermore, the expression of PD-L1 in highly differentiated gastric cancers was higher than that in poorly differentiated cancers (P=0.008). Moreover, the expression of APE1 and PD-L1 in gastric cancers was positively correlated (r=0.336, P<0.01). Multivariate analysis showed that the depth of invasion was a significant prognostic factor (risk ratio 19.91; P=0.000), but there was no significant relationship with PD-L1, APE1, prognosis, and other characteristics.ConclusionThe deregulation of PD-L1 and APE1 might contribute to the development and the poor prognosis of gastric cancer. Our findings suggest that high expression of PD-L1 and APE1 is a risk factor of gastric cancer and a new biomarker to predict the prognosis of gastric cancer. Furthermore, our findings suggest that targeting the PD-L1 and APE1 signaling pathways may be a new strategy for cancer immune therapy and targeted therapy for gastric cancer, especially in patients with deep invasion and lymph node metastasis.

Polymorphism of DNA base excision repair (BER) genes affects DNA repair capacity and may alter sensitivity to platinum-based chemotherapy regimens. This study investigated polymorphisms of OGG1 Ser326Cys, APE1 Asp148Glu APE1-141T/G and XRCC1 Arg399Gln for association with clinical outcome in 235 advanced inoperable nonsmall-cell lung cancer (NSCLC) patients after treatment with platinum-based chemotherapy. The multivariate analysis showed that OGG1 326 GC was associated with poor PFS [hazard ratio (HR) 1.730, p 5 0.005], while XRCC1 399 GA, or GA1AA, was associated with poor OS in short-term period (HR 1.718, p 5 0.003; HR 1.691, p 5 0.003, respectively). Patients with OGG1 326/XRCC1 399 variant alleles had a higher risk to die early in short-term period (HR 1.929, p < 0.001). Furthermore, patients with XRCC1 399 variant allele (GA1AA) had higher risk of hematologic toxicity (p 5 0.009), whereas patients carrying the OGG1 326 variant (GG), or the APE1-141 GG variant, had reduced risk of gastrointestinal toxicity (p 5 0.015 and p 5 0.023, respectively). The data from the current study provide evidence that OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and APE1-141T/G polymorphisms may be useful in predicting clinical outcomes in patients with advanced inoperable NSCLC that will undergo platinum-based chemotherapy.Lung cancer is the leading cause of cancer-related death in the world and in China. 1 Eighty percent of lung cancer patients are diagnosed with nonsmall-cell lung cancer (NSCLC), of which nearly two thirds are diagnosed at the advanced stages (such as stage IIIB or IV), 2 making curative surgery impossible. Currently, platinum-based therapy is the major remedial option for these advanced inoperable NSCLC patients. To determine the optimal regimen for platinumbased therapy, a randomized phase III clinical trial investigated the effects of four different combinations of cisplatin or carboplatin plus paclitaxel, docetaxel or gemcitabine on 1,207 advanced NSCLC patients, and the data showed that the efficacy of each combination was similar with response rates of 30-40%. 3 The therapeutic efficacy of platinum agents is limited by drug resistance and these advanced NSCLC patients have a 5-year survival rate of only 15%. 4,5 Thus, novel approaches are urgently needed for early detection, better chemotherapeutic agents, selection of more responsive patients for the particular chemotherapy and biomarkers to predict drug sensitivity and outcome.To this end, rapid advances in genomic study have provided novel technologies and therapeutic strategies to establish individualized chemotherapy regimens, which could maximize the benefits of chemotherapy and minimize the likelihood of drug toxicity by allowing the selection of each patient for optimal drug and dosages based on the molecular profiles of their tumors. One such study has focused on DNA repair genes and their polymorphisms in patients treated with platinum-based chemotherapies. This is because DNA repair capacity in tumor cells could lead to resistance of ...

Drugs inhibiting the iron scarcity-induced, siderophore-mediated iron scavenging systems of Mycobacterium tuberculosis (Mtb) and Yersinia pestis (Yp) may provide new therapeutic lines of defense. Compounds with structural similarities to siderophores were synthesized and evaluated as antimicrobials against Yp and Mtb under iron limiting conditions, which mimic the iron scarcity these pathogens encounter and must adapt to in the host, and under standard iron rich conditions for comparison. New antimicrobials were identified, some of which warrant exploration as initial leads against potentially novel targets and small-molecule tools to assist in the elucidation of targets specific to iron-scarcity adapted Yp and Mtb. KeywordsSiderophore; Antimicrobial; drug target; Mycobacterium tuberculosis; Yersinia pestis; arylcarbothioamide-pyrazolines Mtb, the etiologic agent of tuberculosis, and Yp, the causative agent of plague and a potential agent of biowarfare and bioterrorism, are pathogens with serious impacts on global public health. MDR tuberculosis is an emerging pandemic and the surfacing of extensive drugresistant (XDR) tuberculosis poses a new global threat. 1,2 Plague is a re-emerging disease and the occurrence of MDR Yp strains and self-transferable Yp plasmids conferring antibiotic resistance raises concerns about future plague control. 3,4 These scenarios underscore the need for expanding the anti-tuberculosis and anti-plague drug repertoires. Anti-infective drugs against in vivo conditionally essential targets may offer novel therapeutic possibilities, help the fight against MDR/XDR strains and the prevention of their selection and dissemination, and increase biodefense preparedness. 5 *Corresponding authors: LENQ: Tel.: +1 212 746 4497, e-mail: leq2001@med.cornell.edu; JV: Tel.: +91-651-2275843, e-mail: venkatesanj@bitmesra.ac.in. † These authors contributed equally Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access, their production is induced under iron scarcity, and they are believed to be required for scavenging iron inside the host, where free iron is scarce (10 −25 -10 −15 M) and pathogens experience iron-limiting conditions. 6,7 The Mtb siderophore-deficient mutant is impaired for growth in macrophages and iron-limiting culture medium. 8 The Mtb mutant lacking the IrtAB ferri-siderophore uptake system is impaired for multiplication in macrophages, mouse lung, and iron-limiting medium. 9 Siderophore system-deficient Yp strains are avirulent in mice infected subcutaneously (a route imitating the fleabite transmission of Yp) and unable t...