Computing cell state discriminates the aberrant hematopoiesis and activated microenvironment in Myelodysplastic syndrome (MDS) through a single cell genomic study.

BACKGROUND: Myelodysplastic syndrome (MDS) is a complicated hematopoietic malignancy characterized by bone marrow (BM) dysplasia with symptoms like anemia, neutropenia, or thrombocytopenia. MDS exhibits considerable heterogeneity in prognosis, with approximately 30% of patients progressing to acute myeloid leukemia (AML). Single cell RNA-sequencing (scRNA-seq) is a new and powerful technique to profile disease landscapes. However, the current available scRNA-seq datasets for MDS are only focused on CD34+ hematopoietic progenitor cells. We argue that using entire BM cell for MDS studies probably will be more informative for understanding the pathophysiology of MDS. METHODS: Five MDS patients and four healthy donors were enrolled in the study. Unsorted cells from BM aspiration were collected for scRNA-seq analysis to profile overall alteration in hematopoiesis. RESULTS: Standard scRNA-seq analysis of unsorted BM cells successfully profiles deficient hematopoiesis in all five MDS patients, with three classified as high-risk and two as low-risk. While no significant increase in mutation burden was observed, high-risk MDS patients exhibited T-cell activation and abnormal myelogenesis at the stages between hematopoietic stem and progenitor cells (HSPC) and granulocyte-macrophage progenitors (GMP). Transcriptional factor analysis on the aberrant myelogenesis suggests that the epigenetic regulator chromatin structural protein-encoding gene HMGA1 is highly activated in the high-risk MDS group and moderately activated in the low-risk MDS group. Perturbation of HMGA1 by CellOracle simulated deficient hematopoiesis in mouse Lineage-negative (Lin-) BM cells. Projecting MDS and AML cells on a BM cell reference by our newly developed MarcoPolo pipeline intuitively visualizes a connection for myeloid leukemia development and abnormalities of hematopoietic hierarchy, indicating that it is technically feasible to integrate all diseased bone marrow cells on a common reference map even when the size of the cohort reaches to 1,000 patients or more. CONCLUSION: Through scRNA-seq analysis on unsorted cells from BM aspiration samples of MDS patients, this study systematically profiled the development abnormalities in hematopoiesis, heterogeneity of risk, and T-cell microenvironment at the single cell level.

Reliability analysis of inertial sensors for testing static balance of 4-to-5-year-old preschoolers.

BACKGROUND: Balance ability is important for preschoolers' motor and physical development. Portable accelerometers can provide resolution tests and identification of preschoolers with balance defects. RESEARCH QUESTION: Despite previous studies on the balance measures of accelerometer tests, there is a lack of complete analyses for preschoolers aged 4-5 years. In this study, we aim to verify the reliability of measuring the static balance of preschoolers in this age range based on inertia sensors for the acceleration and angular velocity moduli. METHODS: Thirty children wore an inertial sensor in the 5th lumbar vertebra and completed four tests, i.e., standing on a firm surface and on a foam surface with open and closed eyes. The standard deviation of the acceleration modulus and root mean square of the angular velocity modulus were calculated. The analysis was based on the intraclass correlation coefficient (ICC) to determine the internal consistency and feasibility. RESULTS: The ICC of the acceleration modulus was between 0.597 and 0.683 (P < 0.01), and the test-retest reliability was medium. The ICC of the angular velocity modulus was between 0.683 and 0.812 (P < 0.01, P < 0.001), and the test-retest reliability was medium to good. The standard error of measurement (SEM) of the acceleration modulus was between 0.001591 and 0.007248 (g), and the SEM% was between 21.24% and 34.12%. The angular velocity modulus SEM values ranged from 1.296 to 3.441 (deg/s), and the SEM% ranged from 25.17% to 33.26%. The difference between the two tests was evenly distributed on both sides of the mean value, and the difference between the test results was within the consistency limit. SIGNIFICANCE: Inertial sensors can be used to evaluate the static balance ability of preschoolers aged 4-5 years. Further, the angular velocity modulus is more reliable than the acceleration modulus.

Second intention healing of nasal ala and dorsum defects in Asians.

BACKGROUND: Reconstruction of defects of nasal ala and dorsum after surgical excision presents a substantial challenge to dermatologic surgeons. Second intention healing is a simple and extremely useful method to optimize cosmesis after skin cancer removal. OBJECTIVES: This study reported the cosmetic outcomes after second intention healing of nasal ala and dorsum defects in Asians, and estimated the time to epithelialization and complete healing. MATERIALS AND METHODS: Fifteen defects (<1 cm in diameter) of the nasal ala and dorsum in 10 patients were allowed to heal by secondary intention. Cosmetic results were evaluated and the time to epithelialization and complete healing were recorded. RESULTS: Cosmetic outcomes were good to excellent in 80% of the defects; defects of the dorsum showed poorer cosmetic results than defects of the ala. The wounds needed 5-17 days (mean 11.3; SD ± 4.18) to complete epithelialization and 10-24 days (mean 17.7; SD ± 4.85) to heal completely. CONCLUSIONS: Second intention healing of small nasal ala and dorsum defects (<1 cm in diameter) in Asians produces satisfactory cosmetic results with a low complication rate.

Ab interno trabeculotomy combined with cataract extraction in eyes with primary open-angle glaucoma.

OBJECTIVE: To investigate the efficacy and safety of ab interno trabeculotomy using the VISCO360® Viscosurgical System (Sight Sciences, Inc., Menlo Park, CA, USA) combined with cataract extraction in the treatment of primary open-angle glaucoma (POAG). METHODS: Patients with POAG who underwent ab interno trabeculotomy combined with cataract extraction were retrospectively analyzed. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), the number of antiglaucomatous medications, and complications were recorded preoperatively and 1 week, 1 month, 3 months, 6 months, 1 year, and 2 years postoperatively. RESULTS: Thirty-four patients (40 eyes) with POAG were included in this study, including 20 men (22 eyes) and 14 women (18 eyes). Compared with the preoperative IOP, the postoperative IOP was significantly lower at each time point. The greatest reduction in IOP was 60.7% at 1 month after surgery. The BCVA was also significantly improved at each postoperative time point. The number of antiglaucomatous medications used by the patients was significantly lower postoperatively than preoperatively. CONCLUSION: Ab interno trabeculotomy combined with cataract extraction is effective and safe for treatment of POAG.

A novel technique for treating atrophic facial scars in Asians using ultra-pulse CO2 laser.

BACKGROUND AND AIMS: Fractional lasers have become increasingly popular for treating atrophic scars, but their effectiveness is limited for deeper scars. We developed a novel technique (manual fractional thermal contraction technology, MFTCT) using an ultra-pulse CO2 laser and evaluated its efficacy and safety for treating atrophic facial scars. METHODS: A total of 44 patients with atrophic facial scars were treated with MFTCT every 8 weeks for 1-4 times. Overall scar improvement was assessed by photographs taken at baseline and 3 months after the last treatment according to the 4-point global assessment scale (GAS) and ECCA grading scale. Improvements in color, distortion, and texture were assessed by the modified Manchester Scar Scale and scored individually from 1 to 4. Pain degrees and adverse reactions during and after treatment were recorded. RESULTS: A total of 44 patients completed the treatment and follow-ups; of them, 89% reported at least 50% overall improvement after the last treatment. The mean ECCA scores fell from 67.50 ± 23.98 to 45.68 ± 18.57 (a 32% improvement), and the change was significant (P = .000). The average score for overall improvement was 3.48. The average scores for color, distortion, and texture were 3.07 ± 0.62, 3.27 ± 0.50, and 3.52 ± 0.51, respectively. Mean pain degree score was 4.27 ± 1.04, and mean erythema duration was 28.43 ± 6.58 days. Some patients developed pigmentation for a few months that resolved with topical treatment. CONCLUSION: Manual fractional thermal contraction technology has definite clinical efficacy in the treatment of atrophic facial scars with fewer adverse reactions and is worth using in the clinical setting.

Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation.

SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migration and apoptosis. Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer. Hence, SHP2 has become a promising target for cancer immunotherapy. In this paper, we reported the identification of compound 1 as SHP2 inhibitor. Fragment-based ligand design, De novo design, ADMET and Molecular docking were performed to explore potential selective SHP2 allosteric inhibitors based on SHP836. The results of docking studies indicated that the selected compounds had higher selective SHP2 inhibition than existing inhibitors. Compound 1 was found to have a novel selectivity against SHP2 with an in vitro enzyme activity IC50 value of 9.97 µM. Fluorescence titration experiment confirmed that compound 1 directly bound to SHP2. Furthermore, the results of binding free energies demonstrated that electrostatic energy was the primary factor in elucidating the mechanism of SHP2 inhibition. Dynamic cross correlation studies also supported the results of docking and molecular dynamics simulation. This series of analyses provided important structural features for designing new selective SHP2 inhibitors as potential drugs and promising candidates for pre-clinical pharmacological investigations.

Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics.

SHP2 is a potential target for the development of novel therapies for SHP2-dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor. A novel class of selective SHP2 allosteric inhibitors was discovered by using the powerful 'SBP', 'ADMET' and 'CDOCKER' techniques. By means of molecular dynamics simulations, it was observed that these novel inhibitors not only had the same function as SHP099 did in inhibiting SHP2, but also had more favorable conformation for binding to the receptor. Thus, this report may provide a new method in discovering novel and selective SHP2 allosteric inhibitors.

3D QSAR Pharmacophore Based Virtual Screening for Identification of Potential Inhibitors for CDC25B.

Owing to its fundamental roles in cell cycle phases, the cell division cycle 25B (CDC25B) was broadly considered as potent clinical drug target for cancers. In this study, 3D QSAR pharmacophore models for CDC25B inhibitors were developed by the module of Hypogen. Three methods (cost analysis, test set prediction, and Fisher's test) were applied to validate that the models could be used to predict the biological activities of compounds. Subsequently, 26 compounds satisfied Lipinski's rule of five were obtained by the virtual screening of the Hypo-1-CDC25B against ZINC databases. It was then discovered that 9 identified molecules had better binding affinity than a known CDC25B inhibitors-compound 1 using docking studies. The molecular dynamics simulations showed that the compound had favorable conformations for binding to the CDC25B. Thus, our findings here would be helpful to discover potent lead compounds for the treatment of cancers.

Exploring the effect of D61G mutation on SHP2 cause gain of function activity by a molecular dynamics study.

Noonan syndrome (NS) is a common autosomal dominant congenital disorder which could cause the congenital cardiopathy and cancer predisposition. Previous studies reported that the knock-in mouse models of the mutant D61G of SHP2 exhibited the major features of NS, which demonstrated that the mutation D61G of SHP2 could cause NS. To explore the effect of D61G mutation on SHP2 and explain the high activity of the mutant, molecular dynamic simulations were performed on wild type (WT) of SHP2 and the mutated SHP2-D61G, respectively. The principal component analysis and dynamic cross-correlation mapping, associated with secondary structure, showed that the D61G mutation affected the motions of two regions (residues Asn 58-Thr 59 and Val 460-His 462) in SHP2 from ß to turn. Moreover, the residue interaction networks analysis, the hydrogen bond occupancy analysis and the binding free energies were calculated to gain detailed insight into the influence of the mutant D61G on the two regions, revealing that the major differences between SHP2-WT and SHP2-D61G were the different interactions between Gly 61 and Gly 462, Gly 61 and Ala 461, Gln 506 and Ile 463, Gly 61 and Asn 58, Ile 463 and Thr 466, Gly 462 and Cys 459. Consequently, our findings here may provide knowledge to understand the increased activity of SHP2 caused by the mutant D61G.

Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors.

PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 µM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules. The generated pharmacophore model revealed that the one RA, three Hyd, and two HBA features play an important role in binding to the active site of the target protein-PTP-MEG2. Docking simulation study indicated that 10a achieved its potency and specificity for PTP-MEG2 by targeting unique nearby peripheral binding pockets and the active site. The absorption, distribution, metabolism and excretion (ADME) predictions showed that the 11 compounds hold high potential to be novel lead compounds for targeting PTP-MEG2. Our findings here can provide a new strategy or useful insights for designing the effective PTP-MEG2 inhibitors.

The expression of S100P increases and promotes cellular proliferation by increasing nuclear translocation of ß-catenin in endometrial cancer.

There is increasing evidence suggesting that S100P has a significant role in cancer, and is associated with poor clinical outcomes. The expression of S100P mRNA and protein in endometrial cancer and normal endometrium tissues was detected by real-time quantitative RT-PCR and immunohistochemistry. Moreover, we reduced the expression of S100P in HEC-1A and Ishikawa endometrial cancer cell lines by siRNA transfection. Based on the reduced S100P mRNA expression, we measured the effects of S100P on cellular proliferation by the cell-counting kit-8. Nuclear ß-catenin protein level was detected by western blotting. Cyclin D1 and c-myc mRNA expression regulated by ß-catenin was detected by real-time quantitative RT-PCR. We found that the expression of S100P mRNA and protein increased in endometrial cancer tissues compared with the normal endometrium. Local S100P expression progressively increased from pathologic differenciation grade 1 to 3. After reducing the S100P expression, the cellular proliferation ability, nuclear ß-catenin protein level, cyclin D1 and c-myc mRNA levels reduced. It indicated that S100P could promote cell proliferation by increasing nuclear translocation of ß-catenin. The expression of S100P mRNA and protein in endometrial cancer significantly increased and is associated with pathologic differenciation grade. S100P may promote endometrial cell proliferation by increasing nuclear translocation of ß-catenin.