The iterative synthesis of oligoarenes via an organoborane-based cross-coupling reaction (i.e., the Suzuki−Miyaura coupling) has been achieved by using a series of “masked” haloarylboronic acids as ...building blocks whose ordinarily reactive boronyl groups are temporarily protected by a new masking group derived from 1,8-diaminonaphthalene.
On the basis of the boron-masking strategy, new divalent cross-coupling modules have been designed for the efficient synthesis of boron-substituted oligoarenes. The modules, i.e., monoprotected o-, ...m-, and p-benzenediboronic acid derivatives, undergo highly selective Suzuki−Miyaura coupling with sp2 iodides, bromides, chlorides, and triflates, affording coupling products in which the protected boronyl groups are left intact.
Optically active chiral organonickel complexes served as efficient chiral initiators for living aromatizing polymerization of 1,2-diisocyanobenzene derivatives, which afford optically active helical ...poly(quinoxaline-2,3-diyl)s up to 84% s.e. (screw-sense excess). In comparison with asymmetric polymerization with the corresponding organopalladium initiators, the nickel initiators show a much greater polymerization rate, while the selectivity remains high. The organonickel initiators can be generated in situ from nickel(0) precursors with the corresponding enantiopure (S,S)-2-(4,5-diphenylimidazolin-2-yl)phenyl chloride, leading to the convenient synthesis of highly stereo-controlled poly(quinoxaline-2,3-diyl)s.
•Ferrite-Rich Portland cement produces denser microstructure at an early age compared with ordinary Portland cement.•Fe-siliceous hydrogarnet is the main Fe-containing phase in the hydrated ...cement.•Fe(III) ions exist as Fe(OH)4− in the high-pH pore solution.•C-S-H adsorbs Fe(OH)4− via surface complexation reaction and around 2 wt% of Fe incorporated C-S-H C-(F)-S-H is produced in the hydrated cement.
The hydration process in ferrite-rich cement (FC) and its pore structure have been investigated by experimental and thermodynamic modelling techniques. X-ray diffraction (XRD)/Rietveld analysis, thermogravimetry (TG), and mercury intrusion porosimetry (MIP) were performed to study the hydration process, pore volume-pore size distributions, and Fe uptake in calcium-silicate-hydrate (C-S-H). Similar phases were found in both FC and ordinary Portland cement (OPC). The hydration degree of FC was higher at the early stage compared with that of OPC; however, the hydration of OPC exceeded that of FC after 14 days because the high amount of C2S in OPC promoted the late hydration. The XRD-TG results revealed relatively similar Fe uptake by C-S-H in both FC and OPC. The thermodynamic model confirmed the formation of a high amount of Fe phases in FC. Moreover, the model predictions agreed well with the experimental results, demonstrating the accuracy of the proposed model for FC.
Abstract
Immune checkpoint inhibitors (ICIs) and other cancer immunotherapies resurge T cell responses that target tumor antigens expressed by cancer cells, particularly tumor neoantigens derived ...from genetic alterations. However, tumors establish immune escape mechanisms during tumor development and progression, including the loss of pre-existing tumor antigens and impaired T cell responses. In the last decade, various strategies to overcome the immune escape mechanisms have been investigated in the clinic to achieve a cure for cancer. Here, we show that a newly emerged immunogenic neoantigen changes the tumor environment and inhibits tumor growth. To develop animal models, we employed a Tet-on gene expression system, in which immunogenic neoantigens including chicken ovalbumin (OVA) and human cancer-testis antigen NY-ESO-1 were newly emerged upon doxycycline (Dox) treatment. MC-38 (colorectal cancer) inducing OVA, CT26 (colorectal cancer) inducing NY-ESO-1 and B16 (melanoma) inducing NY-ESO-1 were developed, and these cell lines were administered into mice. Induction of these model neoantigens by Dox treatment after tumor establishment (approximately 8~10 mm) significantly inhibited tumor growth. The antitumor effects were not observed in nude mice lacking T cells or CD8+ T-cell depleted mice, indicating an important role of CD8+ T cells. Furthermore, PD-1/PD-L1 blockade further enhanced CD8+ T cell responses against the newly emerged immunogenic neoantigens, resulting in a far stronger tumor growth inhibition. We then propose that newly-emerged immunogenic neoantigens are sufficient to induce antitumor effects that can overcome immune escape mechanisms in the tumor microenvironment, thereby inhibiting tumor growth and that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to ICI therapy.
Citation Format: Daisuke Sugiyama, Tomoaki Muramatsu, Takuro Noguchi, Yoshiki Akatsuka, Hiroyoshi Nishikawa. Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1803.
Lung cancers developed in two boys who had been delivered by mothers with cervical cancer. The cancers in the sons resembled the cancers in the mothers histologically and shared oncogenic driver ...mutations and other unique maternal genes not inherited in their germline, but they did not carry a Y chromosome.
Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens ...and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8+ T cells, indicating the critical role of CD8+ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8+ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.
We examined the effect of different embryo developmental stages, culture periods, and media on the cryotolerance of in vitro–produced porcine blastocysts. All media used for in vitro production, ...vitrification, and warming were chemically defined. When in vitro–produced embryos at the blastocyst and expanded blastocyst stages were vitrified using the Cryotop method on Day 5 or 6 (Day 0 = the day of IVF), the survival rate and hatching rate of expanded blastocysts after warming were higher than those of blastocysts. The viability after vitrification and warming of Day-6 embryos cultured in porcine blastocyst medium from Day 5 were higher than that of embryos cultured in porcine zygote medium 5. On the other hand, there were no significant differences on the cryotolerance between Day-5 embryos cultured in porcine zygote medium 5 and those replaced with porcine blastocyst medium on Day 4. There were no significant differences in viability between the embryonic ages of 5 and 6 days after vitrification and warming. When expanded blastocysts vitrified on Day 5 or 6 were surgically transferred to recipient gilts, all three recipients became pregnant in the Day-5 group, whereas only one out of three recipients became pregnant in the Day-6 group. These results indicate that the cryotolerance of porcine in vitro–produced blastocysts after vitrification appears to depend on the embryonic stage, culture period, and medium.
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