The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects.

Metabolic diversity analysis and genome wide assessment of oxalate accumulation in the leaves of rice () cultivars.

Soluble oxalate accumulates in rice leaves, and it causes mineral deficiency and urinary syndrome in livestock that consume the leaves. In our previous study, we found that the oxalate content was higher in the leaves of Koshihikari ( type cultivar) than in those of Takanari ( type cultivar). This difference was seen even when the two cultivars were grown under a high CO concentration, which inhibits oxalate synthesis via photorespiration, suggesting that the difference resulted from genetic factors rather than environmental factors.

The Challenge Initiative: Lessons on Rapid Scale-Up of Family Planning and Adolescent and Youth Sexual and Reproductive Health Services.

The articles in this supplement showcase The Challenge Initiative’s strategies and insights for sustainably scaling evidence-based family planning and adolescent and youth sexual and reproductive health interventions and emphasize the need for multipronged interventions that address the complex web of factors influencing adolescents’ and youth’s access to contraceptive services.

Improving Contraceptive Service Quality and Accessibility for Adolescents and Youth Through Proprietary Patent Medicine Vendors in Four Nigerian States.

Introduction: In Nigeria, health care services and commodities have increasingly been accessed through private sector entities, including retail pharmacies and drug shops (also called proprietary patent medicine vendors [PPMVs]). However, PPMVs cannot provide long-acting or permanent methods, and concerns have been raised about their quality of services and their need to better comply with government regulations. This article describes how The Challenge Initiative's (TCI) family planning program supported 4 state governments in Nigeria to develop a model to strengthen public-private partnerships between PPMVs and primary health centers (PHCs) to leverage PPMVs to provide adolescents and youth with high-quality contraceptive information, services, and referrals to PHCs.

Mosquitoes Possess Specialized Cuticular Proteins That Are Evolutionarily Related to the Elastic Protein Resilin.

Resilin is an elastic protein that is vital to insects' vigorous movement. Canonical resilin proteins possess the R&R Consensus, a chitin-binding domain conserved in a family of cuticular proteins, and highly repetitive sequences conferring elastic properties. In the malaria vector mosquito, , however, a cuticular protein has been found that has an R&R Consensus resembling that of resilin but lacks the repetitive sequences (here, we call it resilin-related or resilin-r).

Genome-wide association study of leaf photosynthesis using a high-throughput gas exchange system in rice.

Enhancing leaf photosynthetic capacity is essential for improving the yield of rice (Oryza sativa L.). Although the exploitation of natural genetic resources is considered a promising approach to enhance photosynthetic capacity, genomic factors related to the genetic diversity of leaf photosynthetic capacity have yet to be fully elucidated due to the limitation of measurement efficiency.

Pimitespib for the treatment of advanced gastrointestinal stromal tumors and other tumors.

Pimitespib (TAS-116) is the first heat shock protein 90 (HSP90) inhibitor approved in Japan, and it is indicated for the treatment of gastrointestinal stromal tumors (GIST) that have progressed after treatment with imatinib, sunitinib and regorafenib. This review describes the preclinical and clinical research with pimitespib, including its mechanism of action, pharmacokinetics, clinical antitumour activity and safety. In a phase III study, pimitespib significantly prolonged progression-free survival compared with placebo (median 2.

TAS0612, a Novel RSK, AKT, and S6K Inhibitor, Exhibits Antitumor Effects in Preclinical Tumor Models.

The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations.

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration.

Assessing Use, Usefulness, and Application of the High Impact Practices in Family Planning Briefs and Strategic Planning Guides.

Background: In global health, persistent barriers and challenges to bridging the gap between research and practice remain critical to address in most health areas. The High Impact Practices (HIPs) briefs and strategic planning guides aim to bridge the know-do gap in family planning (FP) by facilitating research utilization and knowledge sharing and also providing a summary of experiential knowledge from experts. The purpose of this qualitative study was to assess the use, usefulness, and application of these 2 knowledge products developed by the HIP Partnership for decision-makers and implementers in low- and middle-income countries (LMICs).

Additive effects of brimonidine tartrate 0.1%/brinzolamide 1% fixed-dose combination in prostaglandin analog-treated Japanese glaucoma patients.

Purpose: A brimonidine tartrate 0.1%/brinzolamide 1% fixed-dose combination (BBFC) was recently approved for glaucoma and ocular hypertension treatment in Japan. We investigated the efficacy and safety of BBFC used concomitantly with prostaglandin analogs (PG) or a PG/beta-blocker fixed-dose combination (PG/beta FC).

Bacterial Community Composition Under Paddy Conditions Is More Strongly Affected by the Difference in Soil Type than by Field Management.

In this study, we aimed to investigate the effects of soil type and field management on bacterial communities in paddy soils, taking into account the differences in soil physicochemical properties. We collected soil samples from 51 paddy fields in six prefectures in Japan. The paddy fields were managed under organic regimes (26 fields), natural-farming regimes (12 fields), or conventional regimes (13 fields).

[A Long-Term Survival Case of Multiple Liver Metastases from Colon Cancer Treated with Intensive Multimodality Therapy].

A 60-year-old man diagnosed with sigmoid colon cancer was admitted to our hospital. A CT scan revealed multiple liver metastases. The patient was administered 15 courses of FOLFIRI chemotherapy and 15 courses of FOLFIRI plus Cmab chemotherapy.

Modulation of tumor immune microenvironment by TAS-115, a multi-receptor tyrosine kinase inhibitor, promotes antitumor immunity and contributes anti-PD-1 antibody therapy.

TAS-115 is an oral multi-receptor tyrosine kinase inhibitor that strongly inhibits kinases implicated in antitumor immunity, such as colony stimulating factor 1 receptor and vascular endothelial growth factor receptor. Because these kinases are associated with the modulation of immune pathways, we investigated the immunomodulatory activity of TAS-115. An in vitro cytokine assay revealed that TAS-115 upregulated interferon γ (IFNγ) and interleukin-2 secretion by T cells, suggesting that TAS-115 activated T cells.

Characterization of cell line with dedifferentiated GIST-like features established from cecal GIST of familial GIST model mice.

Approximately 40 families with multiple gastrointestinal stromal tumors (GISTs) and germline c-kit gene mutations have been reported. Three knock-in mouse models have been generated, and all the models showed a cecal GIST. In the present study, we established a cell line derived from cecal GIST in a familial GIST model mouse with KIT-Asp818Tyr.

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors.

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited.

Metabolomic analysis of rice brittle culm mutants reveals each mutant- specific metabolic pattern in each organ.

Introduction: Plant cell walls play an important role in providing physical strength and defence against abiotic stress. Rice brittle culm (bc) mutants are a strength-decreased mutant because of abnormal cell walls, and it has been reported that the causative genes of bc mutants affect cell wall composition. However, the metabolic alterations in each organ of bc mutants have remained unknown.

Trabeculectomy Tenon Advancement Technique May Reduce Bleb-Related Infections.

Prcis: Trabeculectomy using the Tenon advancement technique with a fornix-based (FB) conjunctival flap showed avascular bleb formation less frequently and had a significantly lower risk of developing bleb-related infections than trabeculectomy with a limbus-based conjunctival flap.

Purpose: To determine whether the Tenon advancement technique for trabeculectomy with a FB conjunctival flap is effective in preventing bleb-related infections.

Materials And Methods: This was a single-center, nonrandomized retrospective cohort study of 998 eyes from 854 patients with glaucoma who underwent trabeculectomy with mitomycin C.

Variable Direct Electromechanical Properties of As-Electrospun Polystyrene Microfiber Mats with Different Electrospinning Conditions.

As-electrospun microfiber mats comprising atactic polystyrene (aPS), a low-cost commodity polymer, have demonstrated beneficial electromechanical properties. However, the variability of the electromechanical properties of fiber mats produced using different electrospinning conditions has not been investigated. Therefore, herein, the direct electromechanical properties of aPS fiber mats produced using different deposition times () and electrospinning voltages () are investigated.

Draft Genome Sequence of the Cyanobacterium sp. Strain Nb3U1.

We report the 3.5-Mb draft genome sequence of the cyanobacterium sp. strain Nb3U1, which was isolated from a microbial mat sample collected from Nakabusa Hot Spring, Nagano, Japan.