is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that (KL) or (KP) comutations define distinct subgroups of -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 ( < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with -mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free ( < 0.001) and overall ( = 0.0015) survival compared with ; LUAC. Among 924 LUACs, alterations were the only marker significantly associated with PD-L1 negativity in TMB LUAC. The impact of alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In-mutant murine LUAC models, loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify alterations as a major driver of primary resistance to PD-1 blockade in -mutant LUAC. This work identifies alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in-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. .

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.

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.

Dentin‐pulp complex regeneration is a promising alternative treatment for the irreversible pulpitis caused by tooth trauma or dental caries. This process mainly relies on the recruitment of endogenous or the transplanted dental pulp stem cells (DPSCs) to guide dentin‐pulp tissue formation. Platelet‐derived growth factor (PDGF), a well‐known potent mitogenic, angiogenic, and chemoattractive agent, has been widely used in tissue regeneration. However, the mechanisms underlying the therapeutic effects of PDGF on dentin‐pulp complex regeneration are still unclear. In this study, we tested the effect of PDGF‐BB on dentin‐pulp tissue regeneration by establishing PDGF‐BB gene‐modified human dental pulp stem cells (hDPSCs) using a lentivirus. Our results showed that PDGF‐BB can significantly enhance hDPSC proliferation and odontoblastic differentiation. Furthermore, PDGF‐BB and vascular endothelial growth factor (VEGF) secreted by hDPSCs enhanced angiogenesis. The chemoattractive effect of PDGF‐BB on hDPSCs was also confirmed using a Transwell chemotactic migration model. We further determined that PDGF‐BB facilitates hDPSCs migration via the activation of the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway. In vivo, CM‐DiI‐labeled hDPSCs were injected subcutaneously into mice, and our results showed that more labeled cells were recruited to the sites implanted with calcium phosphate cement scaffolds containing PDGF‐BB gene‐modified hDPSCs. Finally, the tissue‐engineered complexes were implanted subcutaneously in mice for 12 weeks, the Lenti‐PDGF group generated more dentin‐like mineralized tissue which showed positive staining for the DSPP protein, similar to tooth dentin tissue, and was surrounded by highly vascularized dental pulp‐like connective tissue. Taken together, our data demonstrated that the PDGF‐BB possesses a powerful function in prompting stem cell‐based dentin‐pulp tissue regeneration. Stem Cells Translational Medicine 2017;6:2126–2134

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of cancer stem cells (CSCs)-mediated post-surgical recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become a new approach for the treatment of HCC. GLA exhibits anti-tumor effects in that it attenuates the proliferation, migration, invasion, and angiogenesis of human cancer cells. However, the functions of GLA in the regulation of CSCs-like properties in HCC cells, and the molecular mechanisms underlying in remain obscure. Here we found that GLA attenuated the CSCs-like properties by the microRNA-148a (miR-148a)-mediated inhibition of transforming growth factor beta (TGF-β)/SMAD2 signal pathway in HCC cell lines (HepG2, Huh-7, and MHCC97H). Indeed, GLA inhibited the activations/expressions of both TGFβ-induced and the endogenous SMAD2. Further, GLA improved the expression of miR-148a in a dose/time-dependent manner. MiR-148a, which targeted the SMAD2-3′UTR, decreased the expression and function of SMAD2. Knockdown of miR-148a abolished the GLA-induced inhibition of TGF-β/SMAD2 signal pathway and the CSCs-like properties in HCC cells. Our study found a novel mechanism that GLA inhibits the CSCs-like properties of HCC cells by miR-148a-mediated inhibition of TGF-β/SMAD2 signal pathway, which may help to identify potential targets for the therapies of HCC.

The scaffold-free cell-sheet technique plays a significant role in stem-cell-based regeneration. Furthermore, growth factors are known to direct stem cell differentiation and enhance tissue regeneration. However, the absence of an effective means to incorporate growth factors into the cell sheets hinders further optimization of the regeneration efficiency. Here, a novel design of magnetically controlled "growth-factor-immobilized cell sheets" is reported. A new Fe O magnetic nanoparticle (MNP) coated with nanoscale graphene oxide (nGO@Fe O ) is developed to label stem cells and deliver growth factors. First, the nGO@Fe O MNPs can be easily swallowed by dental-pulp stem cells (DPSCs) and have no influence on cell viability. Thus, the MNP-labeled cells can be organized via magnetic force to form multilayered cell sheets in different patterns. Second, compared to traditional Fe O nanoparticles, the graphene oxide coating provides plenty of carboxyl groups to bind and deliver growth factors. Therefore, with these nGO@Fe O MNPs, bone-morphogenetic-protein-2 (BMP2) is successfully incorporated into the DPSCs sheets to induce more bone formation. Furthermore, an integrated osteochondral complex is also constructed using a combination of DPSCs/TGFβ3 and DPSCs/BMP2. All these results demonstrate that the new cell-sheet tissue-engineering approach exhibits promising potential for future use in regenerative medicine.

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affect the quality of life of patients. [2] Unlike the external cutaneous membrane, the lining of the oral cavity has a wet and highly dynamic environment, [3] with endogenous saliva and exogenous food and drink continuously bathing the oral mucosa. In addition, chewing, speech, swallowing, and even changes in facial expressions cause movement of the tongue and oral mucosa. These complex challenges typically render local treatment strategies for protective materials and therapeutic drugs ineffective, owing to their short retention on the mucosal surface. [4] Topical agents such as solutions, powders, ointments, polymer films, and hydrogels (e.g., Gengigel) commonly used in clinical settings are diluted or washed away by saliva within 1 h. This is far shorter than the optimal repair time for treating oral mucosal disorders, which require 12-24 h to heal. [4] In addition to meet the fundamental requirements of safety and usability, the ideal oral mucosal repair material should be thin, elastic, and have excellent wet-tissue adhesion to resist 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.