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Objective: We investigated the treatment outcomes of immune checkpoint inhibitor (ICI) with modulated electro-hyperthermia (mEHT) in patients with recurrent gynecologic cancers. Methods: We retrospectively reviewed the medical records of nine patients who underwent ICI treatment combined with mEHT for recurrent gynecologic cancers at single institution. Results: The median age of the patients was 48 years (range, 44-63). Two, 4, and 3 patients presented with cervical, ovarian, and uterine cancers, respectively. The median line of prior chemotherapy was 2 (1-5). Mismatch repair deficient or high microsatellite instable tumor was found in 2 patients, and seven patients' tumor exhibited more than 1 point at combined positive score in programmed cell death ligand-1. Eight patients received pembrolizumab and one received nivolumab with mEHT every two or three times a week in accordance with the timing of the ICI administration. As treatment results, 1 (11%) and 2 (22%) patients showed complete response and partial response, respectively, with a median progression-free survival of 6.5 months (range, 0.7-44.1). Two experienced stable disease and four progressions were observed. The median overall survival was 16.7 months (range, 1.3-44.1). There was no treatment discontinuation due to adverse events or treatment related death. Conclusion: This small number study showed that ICI with mEHT for recurrent gynecologic cancers could be feasible without severe adverse events. [ABSTRACT FROM AUTHOR]

Although several genes have been identified in rice which are functionally equivalent to the flowering time genes in Arabidopsis, primarily genes involved in the photoperiod pathway, little data is available regarding the genes that function in the autonomous pathway in rice. In order to acquire further insight into the control of heading dates in rice, we isolated and conducted an expression analysis on OsFCA, which exhibited 38% sequence homology with Arabidopsis FCA. The N-terminal region of the OsFCA protein appears to be unusually rich in glycine-residues, unlike the N-terminal region found in FCA. However, the genetic structure of OsFCA is, in general, similar to that of FCA. RT-PCR and in silico analyses also showed that alternative splicing and polyadenylation at intron3 were conserved in the genetic expression of OsFCA. We were able to detect α, β, and γ transcripts, but not the δ transcript, of the OsFCA gene. The β and γ transcripts of the OsFCA gene were detected via Northern analysis in the leaves, roots, and flowers of the plant. Flowers in younger stages exhibited higher transcript levels. These data suggest that intron3 may constitute a primary control point in the OsFCA pre-mRNA processing of rice. The overexpression of OsFCA cDNA, driven by the 35S promoter, was shown to partially rescue the late flowering phenotype of the fca mutant, suggesting that the functions of the OsFCA and the FCA are partially overlapped, despite the lack of an apparent FLC homologue in the rice genome. The constitutive expression of OsFCA resulted in no downregulation of FLC, but did result in the weak upregulation of SOC1 in the transgenic Arabidopsis. OsFCA overexpression did not result in a reduction of the γ transcript levels of FCA in the transgenic Arabidopsis either, thereby suggesting that OsFCA had no effects on the autoregulation of ArabidopsisFCA. All of these results imply conservation and divergence in the functions of FCA between rice and Arabidopsis. [ABSTRACT FROM AUTHOR]

Flowering is regulated by an integrated network of several genetic pathways in Arabidopsis. The key genes integrating multiple flowering pathways are FT, SOC1 and LFY. To elucidate the interactions among these integrators, genetic analyses were performed. FT and SOC1 share the common upstream regulators CO, a key component in the long day pathway, and FLC, a flowering repressor integrating autonomous and vernalization pathways. However, the soc1 mutation further delayed the flowering time of long day pathway mutants including ft, demonstrating that SOC1 acts partially independently of FT. Although soc1 did not show an obvious defect in flower meristem determination on its own, it dramatically increased the number of coflorescences in a lfy mutant, which is indicative of a defect in floral initiation. Therefore, double mutant analysis shows that the three integrators have both overlapping and independent functions in the determination of flowering time and floral initiation. The expression analysis showed that FT regulates SOC1 expression, and SOC1 regulates LFY expression, but not vice versa, which is consistent with the fact that FT and LFY have the least overlapping functions among the three integrators. The triple mutation ft soc1 lfy did not block flowering completely under long days, indicating the presence of other integrators. Finally, vernalization accelerated flowering of flc ft soc1 and ft soc1 lfy triple mutants, which shows that the vernalization pathway also has targets other than FLC, FT, SOC1 and LFY. Our genetic analysis reveals the intricate nature of genetic networks for flowering. [ABSTRACT FROM AUTHOR]

Cold induces expression of a number of genes that encode proteins that enhance tolerance to freezing temperatures in plants. A cis-acting element responsive to cold and drought, the C-repeat/dehydration-responsive element (C/DRE), was identified in the Arabidopsis thaliana stress-inducible genes RD29A and COR15a and found in other cold-inducible genes in various plants. C/DRE-binding factor/DRE-binding protein (CBF/DREB) is an essential component of the cold-acclimation response, but the signaling pathways and networks are mostly unknown. Here we used targeted genetic approach to isolate A. thaliana mutants with altered cold-responsive gene expression (acg) and identify ACG1 as a negative regulator of the CBF/DREB pathway. acg1 flowered late and had elevated expression of FLOWERING LOCUS C (FLC), a repressor of flowering encoding a MADS-box protein. We showed that acg1 is a null allele of the autonomous pathway gene FVE. FVE encodes a homolog of the mammalian retinoblastoma-associated protein, a component of a histone deacetylase (HDAC) complex involved in transcriptional repression. We also showed that plants sense intermittent cold stress through FVE and delay flowering with increasing expression of FLC. Dual roles of FVE in regulating the flowering time and the cold response may have an evolutionary advantage for plants by increasing their survival rates. [ABSTRACT FROM AUTHOR]

The MADS box gene, AGAMOUS-LIKE 20 (AGL20), integrates environmental and endogenous flowering signals in Arabidopsis thaliana. In order to determine if its role is conserved in other plants, we isolated AGL20 orthologs from Brassica campestris, Cardamine flexuosa and Draba nemorosa. The putative amino acid sequences of the orthologs were 94 to 97% identical. We analyzed the flowering phenotype and expression level of the AGL20 ortholog in C. flexuosa, a long day plant that does not respond to vernalization. CaAGL20 was more highly expressed in long days than short days and its expression did not change in response to vernalization, indicating that its expression is correlated with flowering time, as in Arabidopsis. When the Brassica AGL20 ortholog was constitutively expressed in sense and antisense orientations using the 35S cauliflower mosaic virus promoter, some of the sense transgenic plants flowered extremely early and some of the antisense plants exhibited delayed flowering. These results suggest that the role of AGL20 is conserved in Crucifers. [ABSTRACT FROM AUTHOR]

Summary The floral transition in Arabidopsis is regulated by at least four flowering pathways: the long-day, autonomous, vernalization, and gibberellin (GA)-dependent pathways. Previously, we reported that the MADS-box transcription factor S UPPRESSOR OF O VEREXPRESSION OF C O 1 (SOC1) integrates the long-day and vernalization/autonomous pathways. Here, we present evidences that SOC1 also integrates signaling from the GA-dependent pathway, a major flowering pathway under non-inductive short days. Under short days, the flowering time of GA-biosynthetic and -signaling mutants was well correlated with the level of SOC1 expression; overexpression of SOC1 rescued the non-flowering phenotype of ga1-3 , and the soc1 null mutant showed reduced sensitivity to GA for flowering. In addition, we show that vernalization-induced repression of FLOWERING LOCUS C (FLC ), an upstream negative regulator of SOC1 , is not sufficient to activate SOC1 ; positive factors are also required. Under short days, the GA pathway provides a positive factor for SOC1 activation. In contrast to SOC1 , the GA pathway does not regulate expression of other flowering integrators FLC and FT . Our results explain why the GA pathway has a strong effect on flowering under short days and how vernalization and GA interact at the molecular level. [ABSTRACT FROM AUTHOR]