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[ABSTRACT] The population with high myopia is growing worldwide, especially in East Asia. In eyes with pathologic myopia, the axial length is elongated and the eyeball’s shape resembles a rugby ball. The posterior pole of the eye has an outpouching structure, and this unique shape is called a posterior staphyloma. The posterior staphyloma affects the pathogenesis of myopic tractional maculopathy (MTM). MTM is caused by traction on the macula and develops retinal schisis, macular hole, and retinal detachment due to a macular hole. The prevention of advanced stages of MTM, such as retinal detachment, is essential. As the tractional force on the retina is mainly caused by posterior staphyloma and posterior vitreous cortex/internal limiting membrane, two approaches, scleral surgery and vitrectomy, are currently used. Although there have been many surgical options for treating eyes with MTM, the standard approach for this pathology is yet to be established. Less invasive surgery is ideal because myopic schisis is an early stage of MTM in patients with relatively good vision, and secondary macular hole and visual decline are sometimes observed after surgery for myopic schisis. We used scleral imbrication and achieved significant visual recovery with less chance of developing a secondary macular hole.

Additional file 1: Figure S1. Binding properties of DS-1594a·succinate. (A) Green sticks represent amino acid residues that form specific interactions (i.e., hydrogen bonds, π-π interactions, and CH-π interactions) with DS-1594a·succinate. (B) The magenta surface shows the solvent-accessible surface calculated from protein atoms within 5 Å from DS-1594a·succinate. DS1594a·succinate and Menin atoms are shown in yellow and green, respectively. The color scheme of the line and stick is the same as that in (A). Figure S2. Induction of differentiation and loss of cKit+ cells by the Menin-MLL1 inhibitor using MLL-AF9–evoked murine AML-like cells. (A) Representative microscopic images of MGG staining of MLL-AF9–evoked murine AML-like cells after 7 days of treatment with DMSO, DS-1594a·HCl (10, 20, 40 nM), or Ara-C (50, 100). (B) Based on the MGG staining images as indicated in (A), the cells were counted and classified into 5 differentiation categories (blast, myelocyte, metamyelocyte, banded neutrophil, neutrophil). (C) Representative images of FCM analysis with the indicated antibodies for MLL-AF9–evoked murine AML-like cells after 7 days of treatment with DMSO, DS-1594a·succinate (10, 20, and 40 nM), or Ara-C (50 and 100 nM). (D) RT‒qPCR was performed in MLL-AF9–evoked murine AML-like cells after treatment with DS-1594a·succinate (10, 20, 40 nM) or Ara-C (50, 100) for 7 days. The expression levels of Kit (Cd117), Itgam (Cd11b), and Ly6g were normalized to that of Actb and compared to those in the DMSO-treated controls (mean ± SD; n=3). (E) FCM analysis with the cKit antibody for MLL-AF9–evoked murine AML-like cells after 4 days of treatment with DMSO or DS-1594a·succinate (1.5, 4.6, 14 and 41 nM). The bars represent the mean ± SD; n=3. MGG, May-Grünwald-Giemsa; AML, acute myeloid leukemia; Ara-C, cytarabine; MLL, mixedlineage leukemia; APC, allophycocyanin; PE, phycoerythrin. Figure S3. Effect of the Menin-MLL1 inhibitor on the induction of CD11b+ differentiation and loss of CD34+/CD38- AML cells in MLL1-r+ AML patient-derived cells in vitro. Patient-derived primary AML cells (AML#8531, NCCHD010, and AML676) were treated for 7 days with DMSO, DS-1594a·succinate, or Ara-C at the indicated concentrations. Representative images of dot plots and histograms in FCM analysis with anti-human CD34/CD38 antibodies (A) and an anti-human CD11b antibody (B) are shown. (C) RT‒qPCR was performed in AML#8531 and AML676 cells after treatment with DS-1594a·succinate (30, 100, 300, nM) or Ara-C (30, 100) for 7 days. The expression levels of CD34 and ITGAM (CD11b) were normalized to that of ACTB and compared to those in the DMSO-treated controls (mean ± SD; n=3). hCD, human CD. Figure S4. Effect of the Menin-MLL1 inhibitor on the induction of differentiation and loss of potential LICs in NPM1c AML patient-derived cells in vitro. Patient-derived primary NPM1c AML cells (AML#7789, AML#7915, AML#7919) were treated for 7 days with the indicated compounds. (A) FCM analysis of CD33+ cells with anti-human CD34 and CD38 antibodies (AML#7789) or viable cells with anti-human CD33 and CD123 antibodies (AML#7915 and AML#7919). (B) FCM analysis of viable cells with an anti-human CD11b antibody. (C) RTqPCR to detect the expression levels of MEIS1 and HOXA9 (mean ± SD; n = 2 [technical replicates]) normalized to those of GAPDH. AML, acute myeloid leukemia; Ara-C, cytarabine; FCM, flow cytometry; hCD, human CD; LIC, leukemia-initiating cell; NPM1c, mutated nucleophosmin 1; PE, phycoerythrin; PerCP, peridinin-chlorophyll protein complex; RT‒qPCR, real-time quantitative PCR. Figure S5. Changes in Menin/MLL1 occupancies in NCCHD010 cells. (A) RNA-seq was performed in MOLM-13 and NCCHD010 cells treated with DS-1594a·succinate for 3 and 7 days, respectively, at the indicated concentrations. The graphs represent the expression levels of the indicated genes compared to those in the DMSO-treated controls (mean ± SD, n=3). (B) ChIP-seq was performed in NCCHD010 cells treated with 500 nM or 5 μM DS-1594a·succinate for 3 days. Normalized coverage tracks of menin, MLL1, H3K79me2, and H3K4me3 ChIP-seq signals (read per million) at selected target genes in NCCHD010 are shown. The peaks around the TSS are shown. Figure S6. Tumor burden in an AML-PDX model (AM7577) treated with the Menin-MLL1 inhibitor. The tumor burdens in the PB, spleens, and BM of AM7577 mice were assessed by the presence of hCD45+ cells at termination (day 35; n = 6 mice per group). AML, acute myeloid leukemia; hCD, human CD; PB, peripheral blood; PDX, patientderived xenograft. Figure S7. In vivo antitumor effect of the Menin-MLL1 inhibitor in the ALL-PDX model (NCCHD007). RTqPCR to assess the mRNA expression levels of human MEIS1, MEF2C, and CDK6 in the bone marrow of NCCHD007 mice 1 day after 28 days of treatment (day 38) with DS1594a·succinate. The expression levels were normalized to human GAPDH mRNA levels (mean ± SD, n = 3). Figure S8. Pharmacokinetics Parameters in Plasma after Single Oral Administration of DS-1594a·succinate to mice. Blood samples were collected at 1, 2, 6, and 24 hours after a single oral administration of DS-1594a·succinate to severe combined immunodeficiency (SCID) mice at 6.25, 12.5, 25, 50, and 100 mg/kg. Values are mean ± standard deviation (n = 3/group). AUC24h, area under the plasma concentration-time curve up to 24 hours; Cmax, maximum plasma concentration; Tmax, time to reach maximum plasma concentration. Figure S9. Hematology in mice treated orally with DS-1594a·succinate for 28 days before a 28-day recovery period. White blood cell count (WBC), neutrophil count (Neutro.), red blood cell count (RBC), hemoglobin concentration (HGB), and platelet count (PLT) were measured in Crl:CD1 (ICR) mice that were orally administered 0 (vehicle control), 30, 100, or 300 mg/kg (DS-1594a·succinate) once daily for 28 consecutive days (end of the dosing period, 10 mice/group). Five animals treated at dose levels of 0 and 300 mg/kg were used to evaluate the reversibility of toxicity during a 28-day recovery period (end of the dosing recovery period, 5 mice/group). Figure S10. The number of the granulocyte/macrophage colony-forming unit (CFU-GM) of CB-CD34+ using MethoCult H4535. The total number of CFU-GM from human cord blood-derived CD34+ cells was counted using microscopy at 12 days post seeding in MethoCult H4535 and treatment with DMSO, DS-1594·HCl or Ara-C. Each circle indicates the CFU-GM number of each plate and bars represent mean value, n = 2. Table S1. Statistics for data collection and phase refinement. Table S2. Antibodies used for FCM in murine MA9 cells. Table S3. Sample types used for FCM in murine MA9 cells. Table S4. Antibodies used for ChIP. Table S5. Antibodies used in FCM analysis of human-derived AML676 and NCCHD010 cells. Table S6. Antibodies used in FCM analysis of human-derived AML#8531, AML#7789, AML#7915, and AML#7919 cells. Table S7. Information on primary patient samples.

Practical image retrieval systems must fully use image databases. We investigated the accuracy of our content-based computer tomography (CT) image retrieval system (CB-CTIRS) for classifying lesion patterns and retrieving similar cases in patients with diffuse lung diseases. The study included 503 individuals, with 328 having diffuse lung disease and 175 having normal chest CT scans. Among the former, we randomly selected ten scans that revealed one of five specific patterns [consolidation, ground-glass opacity (GGO), emphysema, honeycombing, or micronodules: two cases each]. Two radiologists separated the squares into six categories (five abnormal patterns and one normal pattern) to create a reference standard. Subsequently, each square was entered into the CB-CTIRS, and the F-score used to classify squares was determined. Next, we selected 15 cases (three per pattern) among the 503 cases, which served as the query cases. Three other radiologists graded the similarity between the retrieved and query cases using a 5-point grading system, where grade 5 = similar in both the opacity pattern and distribution and 1 = different therein. The F-score was 0.71 for consolidation, 0.63 for GGO, 0.74 for emphysema, 0.61 for honeycombing, 0.15 for micronodules, and 0.67 for normal lung. All three radiologists assigned grade 4 or 5 to 67.7% of retrieved cases with consolidation, emphysema, or honeycombing, and grade 2 or 3 to 67.7% of the retrieved cases with GGO or micronodules. The retrieval accuracy of CB-CTIRS is satisfactory for consolidation, emphysema, and honeycombing but not for GGO or micronodules.