Objective To explore whether the amount of lipocalin-2 in the biofluid could reflect the onset of sepsis-induced acute lung injury (ALI) in mice.
Methods Lipopolysaccharide (LPS, 10 mg/kg) injection or cecal ligation and puncture (CLP) was performed to induce severe sepsis and ALI in C57 BL/6 male mice randomly divided into 5 groups (n=10 in each group):group A (intraperitoneal LPS injection), group B (intravenous LPS injection via tail vein), group C (CLP with 25%of the cecum ligated), group D (CLP with 75%of the cecum ligated), and the control group (6 sham-operation controls plus 4 saline controls). All the mice received volume resuscitation. Measurements of pulmonary morphological and functional alterations were used to identify the presence of experimental ALI. The expressions of lipocalin-2 and interleukin (IL)-6 in serum, bronchoalveolar lavage fluid (BALF), and lung tissue were quantified at both protein and mRNA levels. The overall abilities of lipocalin-2 and IL-6 tests to diagnose sepsis-induced ALI were evaluated by generating receiver operator characteristic curves (ROC) and computing area under curve (AUC).
Results In both group B and group D, most of the“main features”of experimental ALI were reproduced in mice, while group A and group C showed septic syndrome without definite evidence for the presence of ALI. Compared with septic mice without ALI (group A+group C), lipocalin-2 protein expression in septic mice with ALI (group B+group D) was significantly up-regulated in BALF (P<0.01) and in serum (P<0.01), and mRNA expression boosted in lung tissues (all P<0.05). Lipocalin-2 tests performed better than IL-6 tests in recognizing sepsis-induced ALI cases, evidenced by the larger AUC of the former (BALF tests, 0.8800 versus 0.6625;serum tests, 0.8500 versus 0.7000). Using a dual cutoff system to diagnose sepsis-induced ALI, BALF lipocalin-2 test exhibited the highest positive likelihood ratio (13.000) and the lowest negative likelihood ratio (0.077) among the tests of lipocalin-2 and IL-6 in blood and BALF. A statistically significant correlation was found between lipocalin-2 concentration in BALF and that in serum (Spearman r=0.8803, P<0.0001).
Conclusions Lipocalin-2 expression is significantly up-regulated in septic ALI mice compared with those without ALI. Lipocalin-2 tests with a dual cutoff system could be an effective tool in distinguishing experimental ALI cases.

Recent phase I studies have reported single-agent activities of poly (ADP-ribose) polymerase (PARP) inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor (AR) and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.

Improving Biomarker Development and Assessment: Standards for Study Design

Background: The Early Detection Research Network (EDRN), NCI funded and investigator driven, has the mission to evaluate biomarkers for their clinical utilities in cancer risk prediction, diagnosis, early detection, and prognosis. Abundant cancer biomarkers reported in literature yet few are used in clinics. Therefore, the emphasis of the EDRN is biomarker validation. Although schema for a phased approach to development exists and guidelines are available for study reporting, a coherent and comprehensive set of guideline for a definitive biomarker validation study design have not been delineated.Methods: We proposed PROBE study design, Prospective specimen collec-tion and Retrospective Blinded Evaluation, for pivotal definitive evaluation of the accuracy of a classification biomarker. A detailed formulation of all aspects of the design is provided. Four tables itemize aspects that relate to (i) the Clinical Context; (ii) Performance Criteria; (iii) the Biomarker test; and (iv) Study power and termination. Alternative designs and strategies were contrasted to illustrate the merit of PROBE design.Results: The ideas are applied to studies of biomarkers the intended use of which is for disease diagnosis, screening, or prognosis. Two EDRN valida-tion studies (breast cancer and prostate cancer) were used as examples to elucidate PROBE design.Conclusion: Common biases that pervade the biomarker research literaturewould be eliminated if these rigorous standards were followed closely. We urge the adoption of the design as standard of practice for pivotal evaluation of the classification accuracy ofbiomarkers.

Research Progress of Biological Risk Factors for Suicide with Major Depressive Disorder