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.

Acute respiratory distress syndrome (ARDS) is the leading cause of respiratory failure with high morbidity and mortality. Pulmonary surfactant (PS)-based complementary therapies have exhibited potential for ARDS healing and applied as an adjunctive therapy strategy. Coacervate (Coac) has the characteristics of softness, deformability and excellent molecular enrichment properties, and has attracted extensive attention in the biomedical field. Here PS and coacervate were combined for the potential ARDS treatment. The Coac, fabricated from polyallylamine hydrochloride (PAH) and adenosine triphosphate (ATP) by simple mixing, exhibited soft droplet property and high enrichment for dexamethasone sodium phosphate (DSP). To avoid the fusion effect of membraneless coacervate and endow it with biological functions of PS, liposomes with PS-biomimetic lipid components (PS-lipo) were further introduced to construct PS-biomimetic membranized coacervate (DSP@PS-Coac). The DSP@PS-Coac demonstrated high lung targeting effect and significant penetration efficiency after intravenous injection. Furthermore, PS-lipo replenished the endogenous PS pool and facilitated the distribution of DSP in inflammatory cells in the lung. In the ARDS mouse model, PS-Coac and DSP exerted synergetic anti-inflammatory functions, via reducing the recruitment of inflammatory neutrophils and modulating macrophages into anti-inflammatory phenotype. The overall results confirmed that DSP@PS-Coac may provide a promising delivery option for the treatment of ARDS.

Immune checkpoint inhibitors (ICIs) are currently used in the treatment of various tumors and play an important role in tumor treatment, resulting in many adverse reactions related to the immune system. Type 1 diabetes (T1DM) is a rare endocrine system complication, which is rarely reported at present. We report a case of T1DM after using ICIs to treat gastric cancer. The patient was a 34 year old male who developed diabetes ketoacidosis after 206 days of sintilimab monoclonal antibody use, with fasting blood glucose of 15.78 mmol/L and glycosylated hemoglobin of 8.6%. Islet related antibody: Glutamate decarboxylase antibody: 119.2 IU/mL; Insulin antibody:<2 IU/L. Fasting insulin: 0.21 mU/L; Fasting C-peptide: 0.12 μg/L. Through the analysis of patients' clinical data, it aims to improve clinicians' understanding of immune related type 1 diabetes and provide ideas for correct diagnosis and treatment.

Objective:To explore the relationship between cardiac radiation dose and prognosis of patients with non-small cell lung cancer (NSCLC).Methods:From August 2015 to September 2018, the clinical data and cardiac dose parameters of 180 patients with locally advanced NSCLC who received radiotherapy in Tangshan people′s Hospital of Hebei Province were analyzed retrospectively.The relationship between cardiac dose parameters and overall survival rate was analyzed by K-M analysis, and the prognostic factors of NSCLC patients were identified by multivariate Cox regression.Results:The median survival time of NSCLC patients was 33.4 months.Univariate analysis indicated prescription dose≥56Gy ( HR 1.54, 95% CI1.28-2.86, P=0.011), hypertension ( HR 1.42, 95% CI1.34-1.89, P=0.012), mean cardiac dose≥13.9Gy ( HR 1.12, 95% CI1.05-2.61, P=0.031), V5≥70% ( HR 1.08, 95% CI1.01-2.16, P=0.044), and V30≥40% ( HR 1.16, 95% CI1.04-3.01, P=0.041), V50≥20% ( HR 1.23, 95% CI1.11-2.81, P<0.001), and V60≥5% ( HR 1.03, 95% CI1.00-1.89, P=0.037) were the prognostic factors of NSCLC patients.After multi-factor adjustments, receiving chemotherapy was a favorable factor for the prognosis of NSCLC patients ( HR 0.711, 95% CI0.35-0.89, P=0.005); hypertension was a factor of poor prognosis ( HR 1.641, 95% CI1.56-1.86, P=0.034); V50≥20% in cardiac dose ( HR 1.161, 95% CI1.13-3.82, P=0.002) was a poor prognostic factor in NSCLC patients. Conclusion:The cardiac dose V50 is an independent predictor of prognosis in patients with advanced NSCLC.The increase of cardiac radiation dose may increase the potential risk of death.In clinical practice, the prognosis of patients may be improved by reducing the cardiac radiation dose.

Objective To summarize the curative effect of repairing large area soft tissue defects in heel and crus by flaps with double blood-supply of posterior tibial artery perforators and saphenous nerve nutrient vessels.Methods From January 2006 to February 2012,twenty cases took operation under the guide of Continuous Wave Doppler and design of tibial artery perforator as rotation point.And in all cases,island flaps with the blood supply from saphenous nerve nutrient vessels and tibial artery perforator were retained to repair large area soft tissue defects in heel and crus.In operations,the range of flap area were ranged from 19 cm × 11 cm to 11 cm × 8 cm.Skin flaps incision was up to the patella margin level,low to medial malleolus on edge,former to crus former median line,rear to after crus median line and farthest to the surface of wound on the metatarsophalangeal joint.Results Nineteen cases survived,and 1 case of skin flap mild necrosis at the farthest side took a second-phase line skin flap to repair.Followed-up from 6 months to 24 months was taken in all cases at the mean time of 10 months,with a result of good recovery and no ulceration for the flaps.To varying degree,all flaps recover sense of pain and deep touch.Conclusion There is no wound to posterior main tibial artery in repairing large area soft tissue defects in heel and crus by flaps with double blood-supply from posterior tibial artery perforators and saphenous nerve nutrient vessels,meanwhile to maintain double blood-supply from posterior tibial artery perforators and saphenous nerve nutrient vessels and expand the range of blood supply of posterior tibial artery perforators.In this operation,a blood circulation for the flap can be guaranteed so as for a large wound in heel and crus.

Objective To study the expression of tumor necrosis factor alpha (TNF-α) in the intestine of mice irradiated by neutron and γ rays.Methods 350 male BALB/c mice were irradiated with neutron and γ rays of different doses, and sacrificed at 6 and 12hours, 1, 2, 3, 4, 5, 7, 10, 14, 21 and 28 days after irradiation.The TNF-α in the mice intestinal tissue was detected by means of immunohistochemistry and image analysis.Results In normal control mice, TNF-α was expressed in the cytoplasm of macrophages in intestinal villus interstitium, submucosa and lymph tissue.After 2.5Gy neutron radiation, TNF-α was decreased progressively within 2 days, increased obviously in macrophages and crypt cells during 3rd～7th day, reached the peak at 5th day and recovered to normal level at 14th day and TNF-α was decreased progressively within 4 days after 4.0 and 5.5Gy neutron and 12Gy ray irradiation.TNF-α was increased obviously in 6～12 hours, decreased at 1st day, increased at 2nd～5th day, peaked at 3rd day and recovered at 10th day after 5.5Gy ray irradiation.Conclusion Neutron and ray radiation induce different expression profile of endogenous TNF-α in small intestine, which may be related with the pathologic courses of irradiation-induced damage and repair of intestine.