Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.

Double network (DN) hydrogels, a kind of promising soft and tough hydrogels, are produced by two unique contrasting networks with designed network entanglement burst into the field of materials science as versatile functional systems for a very broad range of applications. A part of the DN hydrogels is characterized by extraordinary mechanical properties providing efficient biocompatible and high strength for holding considerable promise in tissue engineering. Following DN hydrogels principles and consideration of biomedical applications, we provide an overall view of the present various DN hydrogels and look forward to the future of DN hydrogels for tissue engineering. In this review, the preparation methods, structure, properties, current situation, and challenges are mainly discussed for the purpose of tissue engineering. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement.

Fully synthetic carbohydrate-based cancer vaccine is an attractive concept, while an important topic in the area is to develop proper vaccine carriers that can improve the immunogenicity and other immunological properties of tumor-associated carbohydrate antigens (TACAs). In this context, four monophosphoryl derivatives of Neisseria meningitidis lipid A were synthesized via a highly convergent and effective strategy and evaluated as vaccine carriers and adjuvants. The conjugates of these monophosphoryl lipid A (MPLA) derivatives with a modified form of the sTn antigen were found to elicit high titers of antigen-specific IgG antibodies, indicating T cell-dependent immune response, in the absence of an external adjuvant. It was concluded that MPLA’s could be utilized as potent vaccine carriers and built-in adjuvants to create fully synthetic self-adjuvanting carbohydrate-based cancer vaccines. The lipid composition and structure of MPLA were shown to have a significant influence on its immunological activity, and among the MPLA’s examined, natural N. meningitidis MPLA exhibited the most promising properties. Moreover, Titermax Gold, a conventional vaccine adjuvant, was revealed to inhibit, rather than promote, the immunological activity of MPLA conjugates, maybe via interacting with MPLA text goes here.

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Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound NP19 inhibited the human PD-1/PD-L1 interaction with IC50 values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, NP19 dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, NP19 displayed significant in vivo antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that NP19 activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows NP19 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.

Fully synthetic, self-adjuvanting monophosphoryl lipid A–globo H conjugate elicited strong T cell-mediated immunity that could target and kill breast cancer.

α-2,9-Polysialic acid is an important capsular polysaccharide expressed by serotype C Neisseria meningitidis. Its protein conjugates are current vaccines against group C meningitis. To address some concerns about traditional protein conjugate vaccines, a new type of fully synthetic vaccines composed of oligosialic acids and glycolipids was explored. In this regard, α-2,9-linked di-, tri-, tetra-, and pentasialic acids were prepared and conjugated with monophosphoryl lipid A (MPLA). Immunological studies of the conjugates in C57BL/6J mouse revealed that they alone elicited robust immune responses comparable to that induced by corresponding protein conjugates plus adjuvant, suggesting the self-adjuvanting properties of MPLA conjugates. The elicited antibodies were mainly IgG2b and IgG2c, suggesting T cell dependent immunities. The antisera had strong and specific binding to α-2,9-oligosialic acids and to group C meningococcal polysaccharide and cell, indicating the ability of antibodies to selectively target the bacteria. The antisera also mediated strong bactericidal activities. Structure–activity relationship analysis of the MPLA conjugates also revealed that the immunogenicity of oligosialic acids decreased with elongated sugar chain, but all tested MPLA conjugates elicited robust immune responses. It is concluded that tri- and tetrasialic acid–MPLA conjugates are worthy of further investigation as the first fully synthetic and self-adjuvanting vaccines against group C meningitis.