Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-B1 and tumor necrosis factor-A signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis.

The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition, 11 also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days, 11 did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception.

BACKGROUND AND PURPOSENeuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized. EXPERIMENTAL APPROACHAgonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests. KEY RESULTSBN-9 acted as a novel multifunctional agonist at μ, δ, κ, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by μ and κ receptor antagonists, but not by the δ receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED 50 value for gastrointestinal transit inhibition compared with the ED 50 values for antinociception. CONCLUSIONS AND IMPLICATIONSBN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.

Objective: The aim of this study was to validate a novel pictorial-based Longshi Scale for evaluating a patient’s disability by healthcare professionals and non-professionals. Design: Prospective study. Setting: Rehabilitation departments from a grade A, class 3 public hospital, a grade B, class 2 public hospital, and a private hospital and seven community rehabilitation centers. Subjects: A total of 618 patients and 251 patients with functional disabilities were recruited in a two-phase study, respectively. Main measures: Outcome measure: pictorial scale of activities of daily living (ADLs, Longshi Scale). Reference measure: Barthel Index. The Spearman correlation coefficient was used to analyze the validity of Longshi Scale against Barthel Index. Results: In phase 1 study, from March 2016 to August 2016, the results demonstrated that the Longshi Scale was both reliable and valid (intraclass correlation coefficient based on two-way random effect (ICC2,1) = 0.877–0.974 for intra-rater reliability; ICC2,1 = 0.928–0.979; κ = 0.679–1.000 for inter-rater reliability; intraclass correlation coefficient based on one-way random effect (ICC1,1) = 0.921–0.984 for test–retest reliability and Spearman correlation coefficient = 0.836–0.899). In the second phase, in March 2018, results further demonstrated that the Longshi Scale had good inter-rater and intra-rater reliability among healthcare professionals and non-professionals including therapists, interns, and personal care aids (ICC1,1 = 0.822–0.882 on Day 1; ICC1,1 = 0.842–0.899 on Day 7 for inter-rater reliability). In addition, the Longshi Scale decreased assessment time significantly, compared with the Barthel Index assessment ( P < 0.01). Conclusion: The Longshi Scale could potentially provide an efficient way for healthcare professionals and non-professionals who may have minimal training to assess the ADLs of functionally disabled patients.

BackgroundWith the increasing of ageing population, tuberculosis in the elderly brings a challenge for the tuberculosis (TB) control in China. Enough social support can promote the treatment adherence and outcome of the elderly patients with TB. Exploring effective interventions to improve the social support of patients is of great significance for TB management and control.MethodsA community-based, repeated measurement trial was conducted. Patients with TB >65 years of age were allocated into the intervention or control group. Patients in the intervention group received comprehensive social support interventions, while those in the control group received health education alone. The social support level of patients was measured at baseline and at the first, third and sixth months during the intervention to assess the effectiveness of comprehensive social support interventions.ResultsA total of 201 patients were recruited into the study. Compared with the control group, social support for patients in the intervention group increased significantly over time (βgroup*time=0.61, P<0.01) in the following three dimensions: objective support (βgroup*time=0.15, P<0.05), subjective support (βgroup*time=0.32, P<0.05) and support utilisation (βgroup*time=0.16, P<0.05). The change in the scores in the control group was not statistically significant.ConclusionsThe intervention programme in communities, including health education, psychotherapy and family and community support interventions, can improve the social support for elderly patients with TB compared with single health education.Trial registration numberChiCTR-IOR-16009232