Local infiltration of HYR-PB21, a sustained-release formulation of bupivacaine, provides analgesia and reduces opioid requirement after haemorrhoidectomy: a randomised controlled trial.

BACKGROUND: HYR-PB21 is a new sustained-release formulation of bupivacaine indicated for controlling postoperative pain. The objectives of this study were to investigate the analgesic efficacy and safety profile of HYR-PB21 in patients after haemorrhoidectomy. METHODS: This was a multicentre, randomised, double-blind, positive-controlled trial. Patients were assigned randomly to receive a single dose of HYR-PB21 (150 mg or 300 mg) or bupivacaine HCl (75 mg) after surgery for prolapsing haemorrhoids. Postoperative pain was evaluated using a numeric rating scale at rest to calculate a cumulative pain score. Total rescue opioid usage and the proportion of subjects receiving rescue opioid were also assessed. RESULTS: We enrolled 72 patients with haemorrhoidectomy, and 71 patients completed the study. The average cumulative pain score through 72 h after surgery in the 300 mg HYR-PB21 group (87 scores) was lower than in the bupivacaine HCl group (166 scores) in an intention-to-treat analysis (P<0.001). There was a dose-response effect in reducing total opioid usage and the proportion of rescue opioid use between the 150 mg and 300 mg HYR-PB21 groups, with bupivacaine HCl as a reference group. The HYR-PB21 groups did not show more adverse effects than the bupivacaine HCl group. CONCLUSIONS: Local infiltration of a single dose of HYR-PB21 sustained-release bupivacaine had better efficacy in controlling postoperative pain, with similar adverse effects, compared with a single dose of bupivacaine HCl in patients after haemorrhoidectomy. CLINICAL TRIAL REGISTRATION: ChiCTR2000041318 (Chinese Clinical Trial Registry).

Nanoparticle/Nanocarrier Formulation as an Antigen: The Immunogenicity and Antigenicity of Itself.

In antibody preparation, the immunogenicity of small molecules is limited due to the instability of adjuvant/hapten emulsions. Nanoparticle-based adjuvants overcome instability and effectively improve immune responses. Immunogenicity and antigenicity are fundamentally important, yet understudied, facets of nanoparticle formulations themselves. Herein, we studied the immunogenicity and antigenicity of nanoparticle formulations. In experiments in a rabbit model, simple inorganic nanoparticle (e.g., gold nanoparticle (AuNP) and silver nanoparticle (AgNP)) immunogens induced higher titers of antiserum. Moreover, several promising nanoparticle drug carrier immunogens (e.g., SiO2, oleylamine graft polysuccinimide (PSIOAm), oleylamine and N-(3-aminopropyl)imidazole cograft polysuccinimide (PSIOAm-NAPI), Fe3O4@O-dextran, etc.) showed excellent immunogenicity. Cross-reactivity calculations revealed that the antigenicity properties of AgNP and AuNP antigens are highly size-dependent. Meanwhile, four nanoparticle drug carriers generate antibody-specific immune responses to their antigens. The reactivity of the anti-NP antibodies with nanoparticle antigens was confirmed using immunoassays. This study systematically identified the immunogenicity and antigenicity of the nanoparticle formulation itself. These findings provide insights into the immunological properties of the nanoparticle formulation itself in an organism.

Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population.

Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are encoded by members of a human multigene family, comprising 11 protein-coding genes and two pseudogenes. Among the LILRs, LILRB3 and LILRA6 show the highest homology with each other, along with high allelic and copy number variations. Therefore, it has been difficult to discriminate between them, both genetically and functionally, precluding disease association studies of LILRB3 and LILRA6. In this study, we carefully performed variant screening of LILRB3 and LILRA6 by cDNA cloning from Japanese individuals and identified four allelic lineages showing significantly high non-synonymous-to-synonymous ratios in pairwise comparisons. Furthermore, the extracellular domains of the LILRB3*JP6 and LILRA6*JP1 alleles were identical at the DNA level, suggesting that gene conversion-like events diversified LILRB3 and LILRA6. To determine the four allelic lineages from genomic DNA, we established a lineage typing method that accurately estimated the four allelic lineages in addition to specific common alleles from genomic DNA. Analysis of LILRA6 copy number variation revealed one, two, and three copies of LILRA6 in the Japanese-in-Tokyo (JPT) population. Flow cytometric analysis showed that an anti-LILRB3 antibody did not recognize the second most common lineage in the Japanese population, indicating significant amino acid differences across the allelic lineages. Taken together, our findings indicate that our lineage typing is useful for classifying the lineage-specific functions of LILRB3 and LILRA6, serving as the basis for disease association studies.

Effects of Autologous Cytokine-Induced Killer Cells Infusion in Colorectal Cancer Patients: A Prospective Study.

AIM: To evaluate the efficacy and safety of postoperative adjuvant immunotherapy with cytokine-induced killer (CIK) cells in combination with chemotherapy (CT) in colorectal cancer (CRC) patients. MATERIALS AND METHODS: A total of 46 patients were randomly assigned to either group 1 (control group) or group 2 (CIK group) using blocked randomization. Both groups received the FOLFOX4 (5-fluorouridine, leucovorin, and oxaliplatin) CT. In the CIK group, patients were given CIK cell infusion after FOLFOX4 CT. Treatment efficacy, adverse effects, and quality of life (QOL) were assessed. RESULTS: During the first 2 years of follow-up, the recurrence rate in the CIK group (26.1%, 6 in 23 cases) was significantly lower than the control group (43.5%, 10 in 23). The survival time was significantly longer in the CIK group (41.9 months, 95% confidence interval [CI]: 38.2-45.7) than in the control group (33.8 months, 95% CI: 28.4-39.2). Although QOL was reduced in both treatment groups, adjuvant CIK cell transfusion significantly improved the QOL in patients with CRC. Toxicity was mild in patients with CIK treatment. CONCLUSIONS: Immunotherapy with CIK cells may serve as an adjuvant treatment in patients with CRC after CT with prolonged survival of patients, limited side-effects, and improved QOL.

Sustained delivery of siRNA/PEI complex from in situ forming hydrogels potently inhibits the proliferation of gastric cancer.

BACKGROUND: Gastric cancer remains a major cause of mortality and morbidity worldwide. In recent years, gene-based therapeutic strategies were confirmed promising in cancer inhibition and attracted great attention. RNA interference (RNAi) is a powerful tool for gene therapy and has been widely employed to aid in treatment for various diseases, especially cancers. However, effective delivery of small interfering RNA (siRNA) to target cells in vivo remains a challenge for that it is prone to degradation and only lasts a few days in rapidly dividing cells. METHODS: Due to its biocompatibility and well-established safety profile, collagen represents a favourable matrix for in-site drug delivery. In the study, collagen hydrogel was used as carriers to test the feasibility of localized and sustained delivery of Id1-targeted siRNA for in vivo gastric cancer inhibition. To enhance the siRNA delivery, cationic polyethylenimine (PEI) was further emplored for scallold modification. The efficacy of siRNA delivery and cancer inhibition were evaluated with multimodality of mehods in vitro and in vivo. RESULTS: Our results showed that addition of polyethylenimine (PEI) to collagen can facilitate entry of Id1-siRNA into target cells, prolong the silencing effect, and further inhibit tumor growth both in vitro and in vivo. CONCLUSION: This collagen-based delivery system may facilitate the pathogenesis elucidation and design of effective therapies against gastric cancer.

Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development.

Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. In this article, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single-chain variable fragment miniAb. Using the tumor-associated Ag her-2/neu extracellular domain, we showed that the coengagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinoma models. Furthermore, four different extracellular domains of her-2/neu could be targeted to B cells to generate Abs against particular domains with different antitumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost, which may be of use not only for cancer therapy but also for infectious agents.