Fei Jiang

Abstract KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822–35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794. This article is highlighted in the In This Issue feature, p. 781

Abstract The redevelopment/regeneration pattern of amputated limbs from a blastema in salamander suggests that enhanced regeneration might be achieved by mimicking the developmental microenvironment. Inspired by the discovery that the expression of magnesium transporter‐1 (MagT1), a selective magnesium (Mg) transporter, is significantly upregulated in the endochondral ossification region of mouse embryos, a Mg‐enriched 3D culture system is proposed to provide an embryonic‐like environment for stem cells. First, the optimum concentration of Mg ions (Mg 2+ ) for creating the osteogenic microenvironment is screened by evaluating MagT1 expression levels, which correspond to the osteogenic differentiation capacity of stem cells. The results reveal that Mg 2+ selectively activates the mitogen‐activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway to stimulate osteogenic differentiation, and Mg 2+ influx via MagT1 is profoundly involved in this process. Then, Mg‐enriched microspheres are fabricated at the appropriate size to ensure the viability of the encapsulated cells. A series of experiments show that the Mg‐enriched microenvironment not only stimulates the osteogenic differentiation of stem cells but also promotes neovascularization. Obvious vascularized bone regeneration is achieved in vivo using these Mg‐enriched cell delivery vehicles. The findings suggest that biomaterials mimicking the developmental microenvironment might be promising tools to enhance tissue regeneration.

The wet and highly dynamic environment of the mouth makes local treatment of oral mucosal diseases challenging. To overcome this, a photo-crosslinking hydrogel adhesive is developed inspired by the success of light-curing techniques in dentistry. The adhesive operates on a fast (within 5 s) phototriggered S-nitrosylation coupling reaction and employs imine anchoring to connect to host tissues. Unlike other often-used clinical agents that adhere weakly and for short durations, this thin, elastic, adhesive, and degradable cyclic o-nitrobenzyl-modified hyaluronic acid gel protects mucosal wounds from disturbance by liquid rinsing, oral movement, and friction for more than 24 h. The results from both rat and pig oral mucosa repair models demonstrate that this new gel adhesive creates a favorable microenvironment for tissue repair and can shorten tissue healing time. This study thus illustrates a therapeutic strategy with the potential to advance the treatment of oral mucosal defects in the clinic.

Employing theranostic nanoparticles, which combine both therapeutic and diagnostic capabilities in one dose, has promise to propel the biomedical field toward personalized medicine. Here we investigate the theranostic properties of topological insulator bismuth selenide (Bi2Se3) in in vivo and in vitro system for the first time. We show that Bi2Se3 nanoplates can absorb near-infrared (NIR) laser light and effectively convert laser energy into heat. Such photothermal conversion property may be due to the unique physical properties of topological insulators. Furthermore, localized and irreversible photothermal ablation of tumors in the mouse model is successfully achieved by using Bi2Se3 nanoplates and NIR laser irradiation. In addition, we also demonstrate that Bi2Se3 nanoplates exhibit strong X-ray attenuation and can be utilized for enhanced X-ray computed tomography imaging of tumor tissue in vivo. This study highlights Bi2Se3 nanoplates could serve as a promising platform for cancer diagnosis and therapy.

Bone tissue engineering has emerged as a promising alternative therapy for patients who suffer bone fractures or defects caused by trauma, congenital diseases or tumours. However, the reconstruction of bone defects combined with osteoporosis remains a great challenge for clinicians and researchers. Based on our previous study, Ca-Si-based bioceramics (MSCs) showed enhanced bone formation capabilities under normal conditions, and strontium was demonstrated to be therapeutic in promoting bone quality in osteoporosis patients. Therefore, in the present study, we attempted to enlarge the application range of MSCs with Sr incorporation in an osteoporotic bone regeneration model to evaluate whether Sr could assist in regeneration outcomes. In vitro readout suggested that Sr-incorporated MSC scaffolds could enhance the expression level of osteogenic and angiogenic markers of osteoporotic bone mesenchymal stem cells (OVX BMSCs). Animal experiments showed a larger new bone area; in particular, there was a tendency for blood vessel formation to be enhanced in the Sr-MSC scaffold group, showing its positive osteogenic capacity in bone regeneration. This study systematically illustrated the effective delivery of a low-cost therapeutic Sr agent in an osteoporotic model and provided new insight into the treatment of bone defects in osteoporosis patients.