Guang Yang

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.

Abstract Clinical translation of therapeutic peptides, particularly those targeting intracellular protein–protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed β‐catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/β‐catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD‐L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide‐derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.

Despite an extensive body of evidence linking UV radiation and melanoma tumorigenesis, a clear mechanistic understanding of this process is still lacking. Because heritable mutations in both INK4a and the nucleotide excision repair (NER) pathway predispose individuals to melanoma development, we set out to test the hypothesis that abrogation of NER, by deletion of the xeroderma pigmentosum C (Xpc) gene, will heighten melanoma photocarcinogenesis in an Ink4a-Arf-deficient background. Experimentally, we generated a strain of mice doubly deficient in Xpc and Ink4a-Arf and subjected wild-type, Xpc-/-Ink4a-Arf+/+, Xpc-/-Ink4a-Arf-/-, and Xpc+/+Ink4a-Arf-/- mice to a single neonatal (day P3) dose of UVB without additional chemical promotion. Indeed, there was a significant increase in the development of dermal spindle/epithelioid cell melanomas in Xpc-/-Ink4a-Arf-/- mice when compared with Xpc+/+Ink4a-Arf-/- mice (P = 0.005); wild-type and Xpc-/-Ink4a-Arf+/+ mice failed to develop tumors. These neoplasms bore a striking histologic resemblance to melanomas that arise in the Tyr-vHRAS/Ink4a-Arf-/- context and often expressed melanocyte differentiation marker Tyrp1, thus supporting their melanocytic origination. All strains, except wild-type mice, developed pigmented and non-pigmented epidermal-derived keratinocytic cysts, whereas Xpc+/+Ink4a-Arf-/- mice exhibited the greatest propensity for squamous cell carcinoma development. We then screened for NRas, HRas, Kras, and BRaf mutations in tumor tissue and detected a higher frequency of rare Kras(Q61) alterations in tumors from Xpc-/-Ink4a-Arf-/- mice compared with Xpc+/+Ink4a-Arf-/- mice (50% versus 7%, P = 0.033). Taken together, results from this novel UV-inducible melanoma model suggest that NER loss, in conjunction with Ink4a-Arf inactivation, can drive melanoma photocarcinogenesis possibly through signature Kras mutagenesis.

Purpose: Recent studies have indicated that Pentraxin-3 (PTX3) is related to invasion, migration and metastasis of gastric cancer cells (GCCs). However, the function of PTX3 in stemness and tumorassociated macrophages (TAMs) polarization in GC has not yet been revealed. Here, we investigated the role of PTX3 in TAMs polarization and stemness in gastric cancer (GC), and further explored the effect of PTX3 on milky spot metastasis of gastric cancer. Methods: PTX3 expression in human gastric cancer tissues was examined with immunohistochemistry (IHC). The influence on stemness of gastric cancer cells was examined by sphere formation assay and western blot. qRT-PCR, IHC and flow cytometry were used to evaluate M1/M2 macrophage signatures. The effects of PTX3 on TAM polarization and milky spots were investigated in vitro and in vivo. The possible mechanism of PTX3 on targeted cytokines and pathway were analyzed by qRT-PCR and western blot. Results: We found that PTX3 was low expressed in gastric carcinoma tissues and associated with stemness and polarization of macrophages. The upregulation of PTX3 inhibited the stemness of GCCs. Furthermore, PTX3 suppressed the polarization of M2 macrophages in the milky spots in vivo and in vitro and inhibited the metastasis of GC into milky spots. PTX3 restrained the expression of interleukin-4 (IL-4) and IL-10 via the inhibition of phosphorylation of the c-Jun N-terminal protein kinase 1/2 (JNK1/2) in GCCs.