The past decades have witnessed great progress in cancer immunotherapy, which has profoundly revolutionized oncology, whereas low patient response rates and potential immune-related adverse events remain major clinical challenges. With the advantages of controlled delivery and modular flexibility, cancer nanomedicine has offered opportunities to strengthen antitumor immune responses and to sensitize tumor to immunotherapy. Furthermore, tumor-microenvironment (TME)-responsive nanomedicine has been demonstrated to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner, increasing patient response rates to immunotherapy and reducing the immune-related side effects simultaneously. Here, the recent progress of TME-responsive nanomedicine for cancer immunotherapy is summarized, which responds to the signals in the TME, such as weak acidity, reductive environment, high-level reactive oxygen species, hypoxia, overexpressed enzymes, and high-level adenosine triphosphate. Moreover, the potential to combine nanomedicine-based therapy and immunotherapeutic strategies to overcome each step of the cancer-immunity cycle and to enhance antitumor effects is discussed. Finally, existing challenges and further perspectives in this rising field with the hope for improved development of clinical applications are discussed.

Highly pathogenic Gram-negative bacteria and their drug resistance are a severe public health threat with high mortality. Gram-negative bacteria are hard to kill due to the complex cell envelopes with low permeability and extra defense mechanisms. It is challenging to treat them with current strategies, mainly including antibiotics, peptides, polymers, and some hybrid materials, which still face the issue of drug resistance, limited antibacterial selectivity, and severe side effects. Together with precise bacteria targeting, synergistic therapeutic modalities, including physical membrane damage and photodynamic eradication, are promising to combat Gram-negative bacteria. Herein, pathogen-specific polymeric antimicrobials were formulated from amphiphilic block copolymers, poly­(butyl methacrylate)-b-poly­(2-(dimethylamino) ethyl methacrylate-co-eosin)-b-ubiquicidin, PBMA-b-P­(DMAEMA-co-EoS)-UBI, in which pathogen-targeting peptide ubiquicidin (UBI) was tethered in the hydrophilic chain terminal, and Eosin-Y was copolymerized in the hydrophilic block. The micelles could selectively adhere to bacteria instead of mammalian cells, inserting into the bacteria membrane to induce physical membrane damage and out-diffusion of intracellular milieu. Furthermore, significant in situ generation of reactive oxygen species was observed upon light irradiation, achieving further photodynamic eradication. Broad-spectrum bacterial inhibition was demonstrated for the polymeric antimicrobials, especially highly opportunistic Gram-negative bacteria, such as Pseudomona aeruginosa (P. aeruginosa) based on the synergy of physical destruction and photodynamic therapy, without detectable resistance. In vivo P. aeruginosa-infected knife injury model and burn model both proved good potency of bacteria eradication and promoted wound healing, which was comparable with commercial antibiotics, yet no risk of drug resistance. It is promising to hurdle the infection and resistance suffered from highly opportunistic bacteria.

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The increased threat of antibiotic resistance has created an urgent need for new strategies. Herein, polyprodrug antimicrobials are proposed to mimic antimicrobial peptides appended with a concurrent drug release property, exhibiting broad-spectrum antibacterial activity and especially high potency to inhibit methicillin-resistant Staphylococcus aureus (MRSA) without inducing resistance. Two series of polyprodrug antimicrobials are fabricated by facile polymerization of triclosan prodrug monomer (TMA) and subsequent quaternization of hydrophilic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA), affording PDMAEMA-b-PTMA and PQDMA-b-PTMA, respectively. Optimized samples with proper hydrophobic ratio are screened out, which exhibit remarkable bacterial inhibition and low hemolysis toward red blood cells. Furthermore, synergistic antibacterial mechanisms contribute to the bacteria killing, including serious membrane damage, increased out-diffusion of cytosolic milieu across the membrane, and intracellular reductive milieu-mediated triclosan release. No detectable resistance is observed for polyprodrug antimicrobials against MRSA, which is demonstrated to be better than commercial triclosan and vancomycin against in vivo MRSA-infected burn models and a promising approach to the hurdle of antibiotic resistance in biomedicine.

BackgroundMany studies investigated the association between alcohol drinking and gastric cancer risk, but the results were controversial. We performed a meta-analysis of observational studies to explore the association.Materials and MethodsWe searched PubMed to identify the relevant studies that reported the association between alcohol drinking and gastric cancer risk up to December 31, 2016. We pooled relative risks (RRs) in random effects model and performed dose-response analysis to quantify the association. Cochran Q test and I2 analyses were used to evaluate the heterogeneity. Meta-regression, subgroup, sensitivity and publication bias analyses were also performed.Results75 studies were included in our study. The pooled RR of high vs low total alcohol drinking was 1.25 (95% CI, 1.15–1.37, P < 0.001), and a nonlinear association was further observed. Subgroup analysis showed that alcohol drinking significantly associated with the risk of gastric noncardia cancer (RR, 1.19; 95% CI, 1.01–1.40, P = 0.033), but not with the risk of gastric cardia cancer (RR, 1.16; 95% CI, 0.98–1.39, P = 0.087). Notably, the pooled RRs of high vs low analyses were 1.13 (95% CI, 1.03–1.24, P = 0.012) for beer drinking, 1.22 (95% CI, 1.06–1.40, P = 0.005) for liquor drinking, and 0.99 (95% CI, 0.84–1.16, P = 0.857) for wine drinking.ConclusionsOur meta-analysis found a nonlinear association between alcohol drinking and gastric cancer risk, and heavy drinking level was strongly related to gastric cancer risk. Beer and liquor had significant positive associations with gastric cancer risk, while wine drinking would not increase gastric cancer risk. These results need to be verified in future research.

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Gastric cancer is a polygenic disease with a high mortality rate worldwide. Although a number of dysregulated genes have been confirmed to be involved in development and progression of gastric cancer, the molecular mechanisms by which this occurs remain unclear. The present study identified that microRNA (miR-28-5p) was involved in the migration and invasion of gastric cancer cells, and was able to affect the prognosis of patients with gastric cancer. Reverse transcription-quantitative polymerase chain reaction analysis indicated that the expression of miR-28-5p was significantly downregulated in gastric cancer tissues, and that patients with higher expression had a good prognosis. miR-28-5p expression was significantly associated with depth of invasion, lymph node metastasis and pathological stage. Gastric cancer cells overexpressing miR-28-5p exhibited a marked reduction of migration and invasion by Transwell and wound scratch assay. The phosphorylation of RAC serine/threonine-protein kinase (AKT), which affected cellular invasion and metastasis, was significantly inhibited by overexpression of miR-28-5p. In conclusion, miR-28-5p is a tumor suppressor that inhibits gastric cancer cell migration and invasion through repressing AKT phosphorylation. miR-28-5p may therefore represent a potential biomarker for the prognosis of gastric cancer and a novel therapeutic target in advanced gastric cancer.