Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

OBJECTIVE To investigate the resistance of clinical isolated strains to the commonly used antibacterials in our hospital 2007-2008.METHODS Clinical isolated strains and sensitivity of drugs were detected by ATB system.The result of drug sensitivity was judged by CLSI standard and analyzed with statistical software WHONET5.3.RESULTS Altogether 3150 strains bacteria were isolated,17.4% were Gram-positive strains and 82.6% were Gram-negative strains,and the top five isolates were Pseudomonas aeruginosa,Escherichia coli,Klebsiella pneumoniae,Acinetobacter baumannii,and Staphylococcus aureus.The reasistance rate of Gram-positive strains to minocycline was 15.4%.Five VRE strains were isolated.Various Enterobacteriaceae bacteria were sensitive to imipenem meropenem,cefoperazone-sulbactam and piperacillin-tazobactam,and their rate was 86.5% to 97.7%.Some of Acinetobacter and Stenotrophomonas maltophilia were multidrug resistant.CONCLUSIONS It is serous that multidrug resistance of isolated strains of the patients exists in our hospital.