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  • Frontiers Media SA  (7)
  • 2020-2024  (7)
  • 1
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    Treatment outcomes of mucosal melanoma of head and neck: Efficacy of immune checkpoint inhibitors for advanced disease
    Frontiers Media SA ; 2022
    In:  Frontiers in Surgery Vol. 9 ( 2022-12-26)
    Details
    In: Frontiers in Surgery, Frontiers Media SA, Vol. 9 ( 2022-12-26)
    Abstract: Head and neck mucosal melanoma (HNMM) is a rare and aggressive subtype of melanoma. HNMM often develops as a recurrent or metastatic disease, and its prognosis is worse than that of cutaneous melanoma. Recent large-scale clinical studies have reported favorable outcomes with immune checkpoint inhibitors (ICIs) for melanoma. However, these clinical trials included only a small number of HNMM cases. This study aimed to estimate treatment outcomes and prognostic predictors of ICIs for advanced HNMM. Methods Cases of advanced HNMM, defined as unresectable or metastatic HNMM at the initial diagnosis (five patients) or development of recurrent/metastatic HNMM after initial treatment (27 patients), were included in this study. Survival analysis and a search for prognostic factors were performed for these 32 patients. Furthermore, the detailed clinical course of patients who received ICI treatment was investigated. Results The median overall survival (OS) of 32 patients with advanced HNMM was 25.3 months. The estimated 1-, 3-, and 5-year OS rates were 68.4%, 42.8%, and 34.3%, respectively. Fourteen patients (43.7%) received ICIs, whereas 18 (56.3%) did not. Univariate analysis showed that ICI treatment was the only factor associated with a better 1-year OS. Patients who received ICI treatment had significantly longer OS (median OS: not reached, 1-year OS: 85.7%) than those who did not (median OS: 11.3 months, 1-year OS: 54.5%). The overall response and disease control rates of patients who received ICI treatment were 50% and 64.3%, respectively. Patients who achieved complete response (CR) or partial response (PR) to ICI treatment survived significantly longer (1-year OS: 100%) than those who did not (1-year OS: 71.4%). Among the five patients who discontinued ICI treatment due to severe immune-related adverse events (irAEs), four did not receive salvage treatments but showed durable treatment effects and survived for 9.8–54.2 months at the end of the follow-up period. Conclusions ICI treatment achieved a favorable OS for advanced HNMM. CR/PR to ICI treatment and discontinuation owing to severe irAEs were favorable predictors of OS.
    Type of Medium: Online Resource
    ISSN: 2296-875X
    URL: Article
    DOI: 10.3389/fsurg.2022.1032626
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2773823-1
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  • 2
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    Image1.TIF
    Frontiers Media SA ; 2021
    In:  Frontiers in Pharmacology Vol. 12 ( 2021-5-3)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 12 ( 2021-5-3)
    Abstract: Pim kinases are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Here in this study, we investigated the preclinical profile of novel pan-Pim kinase inhibitors with imidazopyridazine and thiazolidinedione structure. Imidazopyridazine-thiazolidinediones inhibited activities of Pim kinases with IC 50 values of tens to hundreds nanomolar. With YPC-21440 and/or YPC-21817, which exhibited especially high inhibitory activities against Pim kinases, we investigated in vitro and in vivo activities of imidazopyridazine-thiazolidinediones. In silico analysis of binding mode of YPC-21440 and Pim kinases revealed that it directly bound to ATP-binding pockets of Pim kinases. In the kinase panel tested, YPC-21440 and YPC-21817 were highly specific to Pim kinases. These compounds exerted antiproliferative activities against various cancer cell lines derived from hematological malignancies and solid carcinomas. Furthermore, they suppressed phosphorylation of Pim kinase substrates, arrested cell cycle at the G1 phase, and induced apoptosis in cultured cancer cells. In tumor xenograft models, YPC-21440 methanesulfonate and YPC-21817 methanesulfonate exerted antitumor activities. Furthermore, pharmacodynamic analysis with a xenograft model suggested that YPC-21817 methanesulfonate inhibited Pim kinases in tumors. In conclusion, our data revealed that imidazopyridazine-thiazolidinediones are novel Pim kinases inhibitors, effective on various types of cancer cell lines both in vitro and in vivo .
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2021.672536
    DOI: 10.3389/fphar.2021.672536.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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  • 3
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    A single high-dose irradiation changes accumulation of methotrexate and gene expression levels of SLC and ABC transporters in cancer cells
    Frontiers Media SA ; 2023
    In:  Frontiers in Pharmacology Vol. 13 ( 2023-1-11)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 13 ( 2023-1-11)
    Abstract: Chemoradiotherapy is frequently used to treat cancer. Stereotactic body radiotherapy (SBRT) is a single high-dose radiotherapy used to treat a variety of cancers. The anticancer drug methotrexate (MTX) shows affinity for solute carrier (SLC) and ATP-binding cassette (ABC) transporters. This study investigated relationships between accumulation of methotrexate and gene expression levels of solute carrier and ATP-binding cassette transporters in cancer cells after a single and high-dose X-ray irradiation. Cancer cell lines were selected from lung and cervical cancer cell line that are commonly used for stereotactic body radiotherapy and effective with methotrexate. We examined expression levels of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP1B7, and organic anion transporter (OAT)1 as solute carrier transporters and multidrug resistance-associated protein (MRP)1 and MRP2 as ATP-binding cassette transporters, using real-time polymerase chain reaction and accumulation of 3 H-MTX in cancer cells after 10-Gy irradiation, assuming stereotactic body radiotherapy. Cells were divided into three groups: Control without irradiation; 4 h after irradiation; and 24 h after irradiation. In control, gene expression levels of OAT1 in all cells was below the limit of measurement. After irradiation, gene expression levels of OATP1B1/1B3/1B7 showed changes in each cell line. Gene expression levels of MRP1/2 tended to increase after irradiation. Gene expression levels of OATP1B1/1B3/1B7 were much lower than those of MRP1/2. Accumulation of 3 H-MTX tended to decrease over time after irradiation. Irradiation of cancer cells thus alters gene expression levels of both solute carrier transporters (OATP1B1/1B3/1B7) and ABC transporters (MRP1/2) and decreases accumulation of 3 H-MTX in cancer cells over time due to elevated expression of MRP1/2.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    DOI: 10.3389/fphar.2022.1069321
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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  • 4
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    Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients
    Frontiers Media SA ; 2023
    In:  Frontiers in Medicine Vol. 10 ( 2023-8-10)
    Details
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 10 ( 2023-8-10)
    Abstract: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. Patients and methods The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p   & lt; 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS ( p  = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Conclusion Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    URL: Article
    DOI: 10.3389/fmed.2023.1229937
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2775999-4
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  • 5
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    DataSheet_2.pdf
    Frontiers Media SA ; 2020
    In:  Frontiers in Immunology Vol. 11 ( 2020-12-22)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 11 ( 2020-12-22)
    Abstract: Radioprotective 105 (RP105) (also termed CD180) is an orphan and unconventional Toll-like receptor (TLR) that lacks an intracellular signaling domain. The agonistic anti-RP105 monoclonal antibody (mAb) can cross-link RP105 on B cells, resulting in the proliferation and activation of B cells. Anti-RP105 mAb also has a potent adjuvant effect, providing higher levels of antigen-specific antibodies compared to alum. However, adjuvanticity is required for the covalent link between anti-RP105 mAb and the antigen. This is a possible obstacle to immunization due to the link between anti-RP105 mAb and some antigens, especially multi-transmembrane proteins. We have previously succeeded in inducing rapid and potent recombinant mAbs in mice using antibody gene-based delivery. To simplify the covalent link between anti-RP105 mAb and antigens, we generated genetic constructs of recombinant anti-RP105 mAb (αRP105) bound to the transmembrane domain of the IgG-B cell receptor (TM) (αRP105-TM), which could enable the anti-RP105 mAb to link the antigen via the cell membrane. We confirmed the expression of αRP105-TM and the antigen hemagglutinin, which is a membrane protein of the influenza virus, on the same cell. We also found that αRP105-TM could activate splenic B cells, including both mature and immature cells, depending on the cell surface RP105 in vitro . To evaluate the adjuvanticity of αRP105-TM, we conducted DNA immunization in mice with the plasmids encoding αRP105-TM and hemagglutinin, followed by challenge with an infection of a lethal dose of an influenza virus. We then obtained partially but significantly hemagglutinin-specific antibodies and observed protective effects against a lethal dose of influenza virus infection. The current αRP105-TM might provide adjuvanticity for a vaccine via a simple preparation of the expression plasmids encoding αRP105-TM and of that encoding the target antigen.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2020.606518
    DOI: 10.3389/fimmu.2020.606518.s001
    DOI: 10.3389/fimmu.2020.606518.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2606827-8
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  • 6
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    Table1.XLSX
    Frontiers Media SA ; 2022
    In:  Frontiers in Physiology Vol. 13 ( 2022-5-9)
    Details
    In: Frontiers in Physiology, Frontiers Media SA, Vol. 13 ( 2022-5-9)
    Abstract: Myofibrillogenesis is an essential process for cardiogenesis and is closely related to excitation-contraction coupling and the maintenance of heartbeat. It remains unclear whether the formation of myofibrils and sarcomeres is associated with heartbeat initiation in the early embryonic heart development. Here, we investigated the association between the ultrastructure of myofibrils assessed by transmission electron microscopy and their proteomic profiling assessed by data-independent acquisition mass spectrometry (DIA-MS) in the rat heart primordia before and after heartbeat initiation at embryonic day 10.0, when heartbeat begins in rats, and in the primitive heart tube at embryonic day 11.0. Bundles of myofilaments were scattered in a few cells of the heart primordium after heartbeat initiation, whereas there were no typical sarcomeres in the heart primordia both before and after heartbeat initiation. Sarcomeres with Z-lines were identified in cells of the primitive heart tube, though myofilaments were not aligned. DIA-MS proteome analysis revealed that only 43 proteins were significantly upregulated by more than 2.0 fold among a total of 7,762 detected proteins in the heart primordium after heartbeat initiation compared with that before heartbeat initiation. Indeed, of those upregulated proteins, 12 (27.9%) were constituent proteins of myofibrils and 10 (23.3%) were proteins that were accessories and regulators for myofibrillogenesis, suggesting that upregulated proteins that are associated with heartbeat initiation were enriched in myofibrillogenesis. Collectively, our results suggest that the establishment of heartbeat is induced by development of bundles of myofilaments with upregulated proteins associated with myofibrillogensis, whereas sarcomeres are not required for the initial heartbeat.
    Type of Medium: Online Resource
    ISSN: 1664-042X
    URL: Article
    URL: Article
    DOI: 10.3389/fphys.2022.907924
    DOI: 10.3389/fphys.2022.907924.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2564217-0
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  • 7
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    DataSheet_1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Marine Science Vol. 10 ( 2023-8-30)
    Details
    In: Frontiers in Marine Science, Frontiers Media SA, Vol. 10 ( 2023-8-30)
    Abstract: Ongoing warming and sea-ice reductions in the Arctic can seriously impact cold-water species, such as polar cod ( Boreogadus saida ), necessitating biomonitoring to reveal the ecological consequences. Recent methodological advancements in environmental DNA (eDNA) techniques have increased our ability to conduct ecological monitoring at various locations, including the Arctic. This study aimed to provide an overview of the distribution of polar cod across the Bering and Chukchi Seas by employing species-specific detection of eDNA. First, we successfully developed novel species-specific qPCR assay targeting the mitochondrial D-loop region, which exclusively amplifies eDNA derived from polar cod. Subsequently, polar cod eDNA was detected using the assay from the samples that we collected latitudinally across the study area during the open-water season. Polar cod eDNA was primarily detected in the surface water from the central Chukchi Sea shelf and the northernmost observation line (75°N), which was located on the shelf slope, off the Point Barrow, and in the marginal ice zone. In contrast, only trace amounts of eDNA were detected in the Bering Sea. This pattern corresponded well with the distribution of water masses classified based on environmental conditions. The detection of eDNA in surface water was clearly limited to cold (-1 to 5°C) and low salinity (25–32) water, whereas it was detected in a higher salinity range (32–34) in the middle and bottom layers. These findings are consistent with current knowledge about the distribution and habitat of the polar cod, suggesting that eDNA can be regarded as a reliable tool to replace or supplement conventional methods. Incorporating eDNA techniques into large-scale oceanographic surveys can improve the spatial and temporal resolution of fish species detection with a reasonable sampling effort and will facilitate the continuous monitoring of Arctic ecosystems.
    Type of Medium: Online Resource
    ISSN: 2296-7745
    URL: Article
    URL: Article
    DOI: 10.3389/fmars.2023.1193083
    DOI: 10.3389/fmars.2023.1193083.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2757748-X
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