Real-world effectiveness of third- or later-line treatment in Japanese patients with HER2-positive, unresectable, recurrent or metastatic gastric cancer: a retrospective observational study.

BACKGROUND: Real-world evidence on the preference for and effectiveness of third- or later-line (3L +) monotherapy for HER2-positive gastric cancer is limited in Japan. This study evaluated the utility of nivolumab, irinotecan, and trifluridine/tipiracil (FTD/TPI) monotherapy as 3L + treatment in Japanese patients with HER2-positive gastric/gastroesophageal junction (G/GEJ) cancer who were previously treated with trastuzumab. METHODS: In this multicenter, retrospective, observational study (20 centers), data of eligible patients were extracted from medical records (September 22, 2017-March 31, 2020), with follow-up until June 30, 2020. Outcomes included overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR). RESULTS: Of 127 enrolled patients, the overall analysis population comprised 117 patients (median [range] age, 71 [38-89] years). The most commonly prescribed 3L + monotherapy was nivolumab (n = 100), followed by irinotecan (n = 12) and FTD/TPI (n = 5). The median (95% confidence interval [CI]) OS, rwPFS, and TTF were 6.2 (4.5-8.0), 1.9 (1.5-2.3), and 1.8 (1.5-2.2) months, respectively, at median (range) 150 (25-1007) days of follow-up. The ORR (CR + PR) and DCR were 9.0% (1% + 8%) and 32.0%, respectively. Factors such as higher neutrophil-lymphocyte ratio (≥ 2.54), Glasgow prognostic score (≥ 1), Eastern Cooperative Oncology Group performance status (ECOG PS; ≥ 2), and hepatic metastasis significantly impacted OS. CONCLUSIONS: The observed OS in this study for HER2-positive G/GEJ cancer was shorter than that reported previously, suggesting that the effectiveness of nivolumab, irinotecan, or FTD/TPI as 3L + therapy may be limited.

Validity of the Wide-range Assessment of Vision-related Essential Skills in Japanese Children with Learning Problems.

SIGNIFICANCE: Our study revealed that the validity of a new Japanese visual-perceptual test was acceptable. Visual-perceptual abilities are important to activities of daily living; thus, accurate assessment of visual perception is especially important for children with neurodevelopmental disorders and particularly so for those with learning problems. PURPOSE: Visual perception refers to the process by which one receives visual information through sensory impulses and then translates those impulses into meaning based on a previously developed view of the environment. A problem in Japan is the paucity of visual perception tests that use normative data from children who are native Japanese. The Wide-range Assessment of Vision-related Essential Skills (WAVES), which measures visual perception and eye-hand coordination skills and is based on Japanese normative data, was recently published in Japan. The validity of this test has not been comprehensively established. METHODS: To investigate the validity of the WAVES, we used the Pearson correlation coefficient to calculate the degrees of association among WAVES scaled and index scores compared with Developmental Test of Visual Perception, Third Edition, scores from 108 elementary school children with symptoms of learning problems. Participants were recruited at Osaka Medical College Learning Disability Center and Sakai Seikeikai Learning Disability Center. RESULTS: The concurrent validity of the WAVES was supported by moderate correlation (r = 0.67, P < .01) between the total scores for visual perception and eye-hand coordination index from the WAVES and general visual perception index from the Developmental Test of Visual Perception, Third Edition, even though a correlation analysis of subtests found differences between the two tests. CONCLUSIONS: Our results showed that the indices from the two tests measured nearly the same underlying visual-perceptual constructs and indicated that the WAVES had acceptable levels of concurrent validity.

Prescription Factors Associated with Medication Non-adherence in Japan Assessed from Leftover Drugs in the SETSUYAKU-BAG Campaign: Focus on Oral Antidiabetic Drugs.

BACKGROUND: Medication adherence has an important influence on health outcomes in patients with chronic diseases. However, few studies have been performed in Japan to determine factors related to medication non-adherence. OBJECTIVE: The aim of this study was to identify prescription factors related to medication non-adherence by investigating patient characteristics, all prescriptions, and prescriptions for oral antidiabetic drugs (OADs). METHODS: A retrospective cross-sectional survey of prescription data about implementation of dosing regimen was performed at community pharmacies engaged in appropriate use of leftover drugs. We evaluated the amount of drugs originally prescribed and the reduced amount after use of leftover drugs, and then calculated prescription reduction ratio (PRR). We analyzed prescription factors contributing to non-adherence based on the PRR. RESULTS: Prescription information for 1207 patients was reviewed, revealing that patients were non-adherent to 58% of prescriptions. Lack of a drug copayment, fewer concurrent drugs, and drugs not in single-dose packaging were associated with non-adherence. Among the 1207 patients, 234 prescriptions for diabetes and 452 OAD formulations were included. Forty-seven percent of prescriptions and 29% of the formulations were non-adherent. A higher dosing frequency and preprandial administration were associated with non-adherence. Among the OADs, adherence was lower for α-glucosidase inhibitors and biguanides than for sulfonylureas. CONCLUSIONS: Several factors related to patient characteristics, general drug prescriptions, and OAD prescriptions were associated with non-adherence. Further consideration will be needed to improve adherence to medication in Japan. Health care providers should perform more careful monitoring of adherence in patients with the factors identified by this study.

Landolt ring-shaped epithelial keratopathy: a novel clinical entity of the cornea.

IMPORTANCE: Landolt ring-shaped epithelial keratopathy is a newly identified disease with vesicular changes of unknown origin in the epithelial cells. OBSERVATIONS: Eleven Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium were assessed. The main symptoms of Landolt ring-shaped epithelial keratopathy are foreign-body sensation and photophobia. Slitlamp examination indicates that Landolt ring-shaped lesions located only in the corneal epithelium are randomly distributed and occur unilaterally, bilaterally, or asymmetrically. Small lesions are sometimes connected to each other to form a large Landolt ring in a fractal pattern. Confocal microscopy reveals that the Landolt ring lesions are vesicular changes in the epithelial cells from the basal cell layer to the superficial cell layer without inflammation. The lesions form for weeks to months with sporadic exacerbations and natural remissions with or without treatments. The outcomes do not include epithelial disorders in the affected corneas or visual disruptions. CONCLUSIONS AND RELEVANCE: We describe a new disease entity of unknown origin referred to as Landolt ring-shaped epithelial keratopathy, which is usually bilateral and characterized by specific Landolt ring-shaped focal epithelial lesions with vesicular changes only in the epithelial cells. The disorder has an insidious onset and self-limiting nature despite treatment and should be included in the differential diagnosis of corneal epithelial disorders.

[Development of a vision-related symptom and performance checklist for children].

OBJECTIVE: Visual dysfunctions can cause problems in academic and athletic activities in children with developmental disorders. This research aims to develop a vision-related symptom and performance checklist for children (VSPCL). METHODS: Parents of 115 children with visual dysfunction and 859 typically developed children were recruited to conduct VSPCL. RESULTS: As a result of factor and discrimination analyses, 39 items were selected and divided into four subscales (alpha =.715 approximately alpha =.924). ROC analysis was used to investigate discriminability, revealing high sensitivities (81.3% - 93.5%) and specificities (79.1% - 91.8%) for all subscales. CONCLUSIONS: VSPCL was found to be useful to discriminate symptoms related to visual dysfunctions in children with developmental disorders.

Medicinal flowers. XXXV. Nor-oleanane-type and acylated oleanane-type triterpene saponins from the flower buds of Chinese Camellia japonica and their inhibitory effects on melanogenesis.

The methanolic extract and its 1-butanol-soluble fraction from the flower buds of Camellia japonica, cultivated in Yunnan Province, China, showed inhibitory effects on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells. From the 1-butanol-soluble fraction, a new 28-nor-oleanane-type and three new oleanane-type triterpene saponins, sanchakasaponins A-D, were isolated together with four known triterpene saponins. Their chemical structures were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells and structure-activity relationships of the saponins were investigated.

Medicinal flowers. XXXVI.1) Acylated oleanane-type triterpene saponins with inhibitory effects on melanogenesis from the flower buds of Chinese Camellia japonica.

Four acylated oleanane-type triterpene oligoglycosides, sanchakasaponins E-H, were isolated from the flower buds of Camellia japonica cultivated in Yunnan province, China, together with four known triterpene oligoglycosides. The chemical structures of the new triterpene oligoglycosides were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects of the triterpene oligoglycoside constituents on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells were investigated.

SIZ1 regulation of phosphate starvation-induced root architecture remodeling involves the control of auxin accumulation.

Phosphate (Pi) limitation causes plants to modulate the architecture of their root systems to facilitate the acquisition of Pi. Previously, we reported that the Arabidopsis (Arabidopsis thaliana) SUMO E3 ligase SIZ1 regulates root architecture remodeling in response to Pi limitation; namely, the siz1 mutations cause the inhibition of primary root (PR) elongation and the promotion of lateral root (LR) formation. Here, we present evidence that SIZ1 is involved in the negative regulation of auxin patterning to modulate root system architecture in response to Pi starvation. The siz1 mutations caused greater PR growth inhibition and LR development of seedlings in response to Pi limitation. Similar root phenotypes occurred if Pi-deficient wild-type seedlings were supplemented with auxin. N-1-Naphthylphthalamic acid, an inhibitor of auxin efflux activity, reduced the Pi starvation-induced LR root formation of siz1 seedlings to a level equivalent to that seen in the wild type. Monitoring of the auxin-responsive reporter DR5::uidA indicated that auxin accumulates in PR tips at early stages of the Pi starvation response. Subsequently, DR5::uidA expression was observed in the LR primordia, which was associated with LR elongation. The time-sequential patterning of DR5::uidA expression occurred earlier in the roots of siz1 as compared with the wild type. In addition, microarray analysis revealed that several other auxin-responsive genes, including genes involved in cell wall loosening and biosynthesis, were up-regulated in siz1 relative to wild-type seedlings in response to Pi starvation. Together, these results suggest that SIZ1 negatively regulates Pi starvation-induced root architecture remodeling through the control of auxin patterning.

SIZ1 controls cell growth and plant development in Arabidopsis through salicylic acid.

The post-translational conjugation of small ubiquitin-related modifiers (SUMOs) to other proteins is involved in regulation of many processes in eukaryotic development; although its role in plant development is beginning to be dissected. Previously, we demonstrated that the siz1 mutant, which is impaired in SUMO E3 ligase, showed a dwarf-like shoot phenotype with accumulation of salicylic acid (SA), and the expression of nahG, a bacterial salicylate hydroxylase that catabolizes SA, in siz1 reduced the SA level and suppressed dwarfism. Herein, we provide evidence that the SIZ1 gene controls cell division and elongation through regulation of the SA level. Mature siz1-2 and siz1-3 plants exhibited a dwarf-like shoot phenotype that is attributable to decreased leaf cell volume and number relative to the wild type. Cell division and expansion defects caused by siz1 were also suppressed by the expression of nahG. Expression of XTH8 and XTH31, encoding xyloglucan endotransglycosylase/hydrolase, which are thought to facilitate leaf cell expansion, was down-regulated in siz1 leaves. However, reduced XTH8 and XTH31 expression in siz1 plants was restored in nahG siz1-2 plants. These results indicate that SIZ1 regulates cell growth and plant development with regulation of SA accumulation. Also, XTH8 and XTH31 genes may be responsible for reduced leaf cell expansion.

Sumoylation of ABI5 by the Arabidopsis SUMO E3 ligase SIZ1 negatively regulates abscisic acid signaling.

SUMO (small ubiquitin-related modifier) conjugation (i.e., sumoylation) to protein substrates is a reversible posttranslational modification that regulates signaling by modulating transcription factor activity. This paper presents evidence that the SUMO E3 ligase SIZ1 negatively regulates abscisic acid (ABA) signaling, which is dependent on the bZIP transcripton factor ABI5. Loss-of-function T-DNA insertion siz1-2 and siz1-3 mutations caused ABA hypersensitivity for seed germination arrest and seedling primary root growth inhibition. Furthermore, expression of genes that are ABA-responsive through ABI5-dependent signaling (e.g., RD29A, Rd29B, AtEm6, RAB18, ADH1) was hyperinduced by the hormone in siz1 seedlings. abi5-4 suppressed ABA hypersensitivity caused by siz1 (siz1-2 abi5-4), demonstrating an epistatic genetic interaction between SIZ1 and ABI5. A K391R substitution in ABI5 [ABI5(K391R)] blocked SIZ1-mediated sumoylation of the transcription factor in vitro and in Arabidopsis protoplasts, indicating that ABI5 is sumoylated through SIZ1 and that K391 is the principal site for SUMO conjugation. In abi5-4 plants, ABI5(K391R) expression caused greater ABA hypersensitivity (gene expression, seed germination arrest and primary root growth inhibition) compared with ABI5 expression. Together, these results establish that SIZ1-dependent sumoylation of ABI5 attenuates ABA signaling. The double mutant siz1-2 afp-1 exhibited even greater ABA sensitivity than the single mutant siz1, suggesting that SIZ1 represses ABI5 signaling function independent of AFP1.

Enhanced efficacy of regulatory T cell transfer against increasing resistance, by elevated Foxp3 expression induced in arthritic murine hosts.

OBJECTIVE: To investigate the efficacy of type II collagen-reactive Foxp3-expressing T cell transfer in suppressing collagen-induced arthritis (CIA) in relation to disease progression. METHODS: CD3-activated CD4 T cells were retrovirally transduced with the Foxp3 gene, and their in vitro suppressive activity on T cell proliferation was assessed for correlation with Foxp3 levels. To suppress CIA, Foxp3-transduced T cells generated with type II collagen- or ovalbumin (OVA)-pulsed dendritic cells (DCs), which were fractionated by Foxp3 levels, were adoptively transferred to mice at various time points. RESULTS: The in vitro suppressive activity of Foxp3-transduced cells correlated positively with Foxp3 levels. Type II collagen-reactive, but not OVA-reactive, Foxp3-transduced cells significantly suppressed CIA when they were transferred before immunization, and this suppression was accompanied by decreased anti-type II collagen antibody production. Larger cell numbers were required to suppress CIA when transfer occurred 20 days after immunization, indicating that hosts became resistant to suppression. Transfer of 1 x 10(5) Foxp3(low) cells had only a marginal effect on CIA suppression in immunized hosts, while transfer of Foxp3(high) cells at smaller doses significantly suppressed CIA. Transfer of 1 x 10(5) Foxp3(high) cells after establishment of arthritis attenuated disease progression but did not reverse joint swelling. CONCLUSION: Resistance to Foxp3-transduced T cells proceeded as CIA progressed, suggesting that late-stage aggressive arthritis is more resistant to regulatory T cell transfer. An elevated expression level of Foxp3 in type II collagen-specific T cells improved their suppressive function in CIA. Thus, transfer of T cells expressing high levels of Foxp3 could be a strategy to overcome the induced resistance to regulatory T cell therapy.

SIZ1-mediated sumoylation of ICE1 controls CBF3/DREB1A expression and freezing tolerance in Arabidopsis.

SIZ1 is a SUMO E3 ligase that facilitates conjugation of SUMO to protein substrates. siz1-2 and siz1-3 T-DNA insertion alleles that caused freezing and chilling sensitivities were complemented genetically by expressing SIZ1, indicating that the SIZ1 is a controller of low temperature adaptation in plants. Cold-induced expression of CBF/DREB1, particularly of CBF3/DREB1A, and of the regulon genes was repressed by siz1. siz1 did not affect expression of ICE1, which encodes a MYC transcription factor that is a controller of CBF3/DREB1A. A K393R substitution in ICE1 [ICE1(K393R)] blocked SIZ1-mediated sumoylation in vitro and in protoplasts identifying the K393 residue as the principal site of SUMO conjugation. SIZ1-dependent sumoylation of ICE1 in protoplasts was moderately induced by cold. Sumoylation of recombinant ICE1 reduced polyubiquitination of the protein in vitro. ICE1(K393R) expression in wild-type plants repressed cold-induced CBF3/DREB1A expression and increased freezing sensitivity. Furthermore, expression of ICE1(K393R) induced transcript accumulation of MYB15, which encodes a MYB transcription factor that is a negative regulator of CBF/DREB1. SIZ1-dependent sumoylation of ICE1 may activate and/or stabilize the protein, facilitating expression of CBF3/DREB1A and repression of MYB15, leading to low temperature tolerance.

Contribution of ferrous iron to maintenance of the gastric colonization of Helicobacter pylori in miniature pigs.

Our previous study showed that the colonization levels of Helicobacter pylori were higher in the stomachs of 5-day-old miniature pigs than in 2-week-old ones. As dietary factors can cause these differences, we compared two diets, i.e., Weanymilk and a similar formula with a higher concentration of Fe(II), Weanylobulin. The colonization levels in the fundic mucosa were significantly higher in 2-week-old pigs fed Weanylobulin than in those fed Weanymilk. Supplementing Weanylobulin with an iron chelator, deferoxamine mesylate, significantly lowered the bacteria counts in the gastric mucosa. Normal diets supplemented with Fe(II) in 2-month-old pigs caused significantly more sites of bacteria in the antrum compared with normal diets alone. In addition, ranitidine, an inhibitor of gastric acid secretion that reduces Fe(III) to Fe(II) in the stomach, decreased the bacteria counts in 10-month-old pigs. These results suggested that Fe(II) maintained the colonization levels of H. pylori in the stomach of the miniature pigs.