The quantitative parameters based on marrow metabolism derived from synthetic MRI: A pilot study of prognostic value in participants with newly diagnosed multiple myeloma.

BACKGROUND: The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International Staging System (R-ISS) in participants with multiple myeloma (MM) is unknown. METHODS: We prospectively enrolled participants with newly diagnosed MM before treatment. The SyMRI of lumbar marrow was used to calculate T1, T2, and PD values and the clinical features were collected. All participants were divided into good response (≥VGPR) and poor response (

Quantitative tumor burden imaging parameters of the spleen at MRI for predicting treatment response in patients with acute leukemia.

Objectives: To study the value of standardized volume and intravoxel incoherent motion (IVIM) parameters of the spleen based on tumor burden for predicting treatment response in newly diagnosed acute leukemia (AL). Methods: Patients with newly diagnosed AL were recruited and underwent abdominal IVIM diffusion-weighted imaging within one week before the first induction chemotherapy. Quantitative parameters of magnetic resonance imaging (MRI) included the standardized volume (representing volumetric tumor burden) and IVIM parameters (standard apparent diffusion coefficient [sADC]; pure diffusion coefficient [D]; pseudo-diffusion coefficient [D∗]; and pseudo-perfusion fraction [f], representing functional tumor burden) of the spleen. Clinical biomarkers of tumor burden were collected. Patients were divided into complete remission (CR) and non-CR groups according to the treatment response after the first standardized induction chemotherapy, and the MRI and clinical parameters were compared between the two groups. The correlations of MRI parameters with clinical biomarkers were analyzed. Multivariate logistic regression was performed to determine the independent predictors for treatment response. Receiver operating characteristic curves were used to analyze the predicted performance. Results: 76 AL patients (CR: n = 43; non-CR: n = 33) were evaluated. Standardized spleen volume, sADC, D, f, white blood cell counts, and lactate dehydrogenase were significantly different between CR and non-CR groups (all p < 0.05). Standardized spleen volume, sADC, and D were correlated with white blood cell and lactate dehydrogenase, and f was correlated with lactate dehydrogenase (all p < 0.05). Standardized spleen volume (hazard ratio = 4.055, p = 0.042), D (hazard ratio = 0.991, p = 0.027), and f (hazard ratio = 1.142, p = 0.008) were independent predictors for treatment response, and the combination of standardized spleen volume, D, and f showed more favorable discrimination (area under the curve = 0.856) than individual predictors. Conclusion: Standardized volume, D, and f of the spleen could be used to predict treatment response in newly diagnosed AL, and the combination of morphological and functional parameters would further improve the predicted performance. IVIM parameters of the spleen may be viable indicators for evaluating functional tumor burden in AL.

Remodeling of the periodontal ligament and alveolar bone during axial tooth movement in mice with type 1 diabetes.

Objectives: To observe the elongation of the axial tooth movement in the unopposed rodent molar model with type 1 diabetes mellitus and explore the pathological changes of periodontal ligament and alveolar bone, and their correlation with tooth axial movement. Methods: The 80 C57BL/6J mice were randomly divided into the streptozotocin(STZ)-injected group (n = 50) and the control group (n = 30). Mice in the streptozotocin(STZ)-injected group were injected intraperitoneal with streptozotocin (STZ), and mice in the control group were given intraperitoneal injection of equal doses of sodium citrate buffer. Thirty mice were randomly selected from the successful models as the T1DM group. The right maxillary molar teeth of mice were extracted under anesthesia, and allowed mandibular molars to super-erupt. Mice were sacrificed at 0, 3, 6,9, and 12 days. Tooth elongation and bone mineral density (BMD) were evaluated by micro-CT analysis(0,and 12 days mice). Conventional HE staining, Masson staining and TRAP staining were used to observe the changes in periodontal tissue(0, 3, 6, 9, and 12 days mice). The expression differences of SPARC, FGF9, BMP4, NOGGIN, and type I collagen were analyzed by RT-qPCR. Results: After 12 days of tooth extraction, our data showed significant super-eruption of mandibular mouse molars of the two groups. The amount of molar super-eruption in the T1DM group was 0.055mm( ± 0.014mm), and in the control group was 0.157( ± 0.017mm). The elongation of the T1DM mice was less than that of the control mice(P<0.001). It was observed that the osteoclasts and BMD increased gradually in both groups over time. Compared with the control group, the collagen arrangement was more disordered, the number of osteoclasts was higher (P<0.05), and the increase of bone mineral density was lower(2.180 ± 0.007g/cm3 vs. 2.204 ± 0.006g/cm3, P<0.001) in the T1DM group. The relative expression of SPARC, FGF9, BMP4, and type I collagen in the two groups increased with the extension of tooth extraction time while NOGGIN decreased. The relative expression of all of SPARC, FGF9, BMP4, and type I collagen in the T1DM group were significantly lower, and the expression of NOGGIN was higher than that in the control group (P<0.05). Conclusion: The axial tooth movement was inhibited in type 1 diabetic mice. The result may be associated with the changes of periodontal ligament osteoclastogenic effects and alveolar bone remodeling regulated by the extracellular matrix and osteogenesis-related factors.

Quantitative IVIM parameters evaluating perfusion changes in brain parenchyma in patients newly diagnosed with acute leukemia: Compared with healthy participants.

Purpose: To study the value of quantitative IVIM parameters in evaluating cerebral blood perfusion changes in patients newly diagnosed with acute leukemia (AL) by comparing them with healthy participants. Materials and methods: This prospective study consecutively recruited 49 participants with newly diagnosed AL and 40 normal controls between July 2020 and September 2022. All participants underwent an MRI of the brain using an axial T1-weighted and an IVIM sequence. The IVIM parameters (water diffusion coefficient, sADC, pseudoperfusion fraction, f; diffusion coefficient, D, pseudodiffusion coefficient, D *, and perfusion-diffusion ratio, PDR) and peripheral white blood cell (WBC) counts were obtained. An unpaired t-test or the Mann-Whitney U-test was performed to compare the differences in gray matter (GM) and white matter (WM) of healthy participants and AL patients and the differences in IVIM parameters between healthy participants and patients with AL. In addition, multivariate (logistic regression) analyses were used to identify independent predictors and then, the receiver operating characteristic curve (ROC) analyses were performed. Results: 40 healthy participants and 49 patients with newly diagnosed AL were evaluated. In healthy participants, sADC, PDR, D and f values of GM were significantly higher than those of WM (t = 5.844, t = 3.838, t = 7.711, z = -2.184, respectively, all P < 0.05). In AL patients, the D, f and sADC values of GM were significantly higher than those of WM (t = 3.450, t = 6.262, t = 4.053, respectively, all P < 0.05). The sADC and f value from AL patients were significantly lower than those from healthy participants in GM (z = -2.537, P = 0.011; and z = -2.583, P = 0.010, respectively) and WM (z = -2.969, P = 0.003; z = -2.923, P = 0.003, respectively). The WBC counts of AL patients were significantly higher than those of healthy participants (t = 3.147, P = 0.002). Multivariate analyses showed that the f values of GM and WM were independent predictors of AL (P = 0.030, and 0.010, respectively), with the optimal cut-off value at 7.08% (AUC ROC curve: 0.661, specificity: 11.4%, sensitivity: 98%) and 13.77% (AUC ROC curve: 0.682, specificity: 79.5%, sensitivity: 59.2%). Conclusion: The IVIM parameters of brain parenchyma in patients newly diagnosed with AL differed from those of the healthy participants. The changes of cerebral blood flow perfusion are expected to provide new ideas for studying central nervous system infiltration in AL.

YAP promotes ocular neovascularization by modifying PFKFB3-driven endothelial glycolysis.

Ocular neovascularization is the leading cause of vision impairment in a variety of ocular diseases, such as age-related macular degeneration and retinopathy of prematurity. Emerging studies have suggested that the yes-associated protein (YAP), a downstream effector of the Hippo pathway, is involved in the pathological angiogenesis, but the mechanism are largely unknown. Here, we demonstrated that hypoxic treatment triggered YAP expression and nuclear translocation in human umbilical vein endothelial cells (HUVECs). YAP acted as a transcriptional co-activator working together with transcriptional enhancer activator domain 1 (TEAD1) to binds the promoter of the key glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3), and thereby increases PFKFB3 expression. Moreover, silencing of YAP inhibited glycolysis as well as proliferation, migration, sprouting and tube formation of HUVECs under hypoxia, all of which could be reversed by enforced expression of PFKFB3. Finally, our animal study also showed that intravitreal injection of small interfering RNA of YAP or PFKFB3 dramatically suppressed the neovascular growth in mouse models of choroidal neovascularization and oxygen-induced retinopathy. These findings provide new insights into a previously unrecognized effect of YAP on endothelial glycolysis and highlight the potential of targeting YAP/PFKFB3 axis in the treatment of ocular neovascularization.

Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension.

Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertension (COH), accompanied by activation of Rac1, a member of the Rho family. Rac1 conditional knockout (Rac1 cKO) in RGCs attenuated RGC apoptosis, in addition to blocking the increase in the number of autophagosomes and the expression of autophagy-related proteins (Beclin1, LC3-II/I, and p62) in COH retinas. Electron micrograph and double immunostaining of LAMP1 and LC3B showed that Rac1 cKO accelerated autolysosome fusion in RGC axons of COH mice. Inhibiting the first autophagic peak with 3-methyladenine or Atg13 siRNA reduced RGC apoptosis, whereas inhibiting the second autophagic peak with 3-MA or blocking autophagic flux by chloroquine increased RGC apoptosis. Furthermore, Rac1 cKO reduced the number of autophagosomes and apoptotic RGCs induced by rapamycin injected intravitreally, which suggests that Rac1 negatively regulates mTOR activity. Moreover, Rac1 deletion decreased Bak expression and did not interfere with the interaction of Beclin1 and Bcl-2 or Bak in COH retinas. In conclusion, autophagy promotes RGC apoptosis in the early stages of glaucoma and results in autophagic cell death in later stages. Rac1 deletion alleviates RGC damage by regulating the cross talk between autophagy and apoptosis through mTOR/Beclin1-Bak. Interfering with the Rac1/mTOR signaling pathway may provide a new strategy for treating glaucoma.

Activated ephrinA3/EphA4 forward signaling induces retinal ganglion cell apoptosis in experimental glaucoma.

Previous studies have demonstrated that EphA4 participates in neuronal injury, and there is a strong interaction between ephrinA3 and EphA4. In this study, we showed that in a rat chronic ocular hypertension (COH) experimental glaucoma model, expression of EphA4 and ephrinA3 proteins was increased in retinal cells, including retinal ganglion cells (RGCs) and Müller cells, which may result in ephrinA3/EphA4 forward signaling activation on RGCs, as evidenced by increased p-EphA4/EphA4 ratio. Intravitreal injection of ephrinA3-Fc, an activator of EphA4, mimicked the effect of COH on p-EphA4/EphA4 and induced an increase in TUNEL-positive signals in normal retinas, which was accompanied by dendritic spine retraction and thinner dendrites in RGCs. Furthermore, Intravitreal injection of ephrinA3-Fc increased the levels of phosphorylated src and GluA2 (p-src and p-GluA2). Co-immunoprecipitation assay demonstrated interactions between EphA4, p-src and GluA2. Intravitreal injection of ephrinA3-Fc reduced the expression of GluA2 proteins on the surface of normal retinal cells, which was prevented by intravitreal injection of PP2, an inhibitor of src-family tyrosine kinases. Pre-injection of PP2 or the Ca2+-permeable GluA2-lacking AMPA receptor inhibitor Naspm significantly and partially reduced the number of TUNEL-positive RGCs in the ephrinA3-Fc-injected and COH retinas. Our results suggest that activated ephrinA3/EphA4 forward signaling promoted GluA2 endocytosis, then resulted in dendritic spine retraction of RGCs, thus contributing to RGC apoptosis in COH rats. Attenuation of the strength of ephrinA/EphA signaling in an appropriate manner may be an effective way for preventing the loss of RGCs in glaucoma.

Ocular Biometric Characteristics of Chinese with History of Acute Angle Closure.

PURPOSE: To investigate the biometric characteristics of Chinese patients with a history of acute angle closure (AAC). METHODS: In this clinic-based, retrospective, observational, cross-sectional study, biometric parameters of eyes were acquired from a general population of Chinese adults. The crowding value (defined as lens thickness (LT); central corneal thickness (CCT); anterior chamber depth (ACD)/axial length (AL)) was calculated for each patient. Logistic regression analysis was performed to identify risk factors for AAC. Receiver operating characteristic (ROC) curves were plotted, and biometric variables were compared to compile a risk assessment for AAC. RESULT: This study included 1500 healthy subjects (2624 eyes, mean age of 66.54 ± 15.82 years) and 107 subjects with AAC (202 eyes, mean age of 70.01 ± 11.05 years). Eyes with AAC had thicker lens (P ≤ 0.001), shallower anterior chamber depth (P ≤ 0.001), and shorter axial length (P ≤ 0.001) than healthy eyes. Logistic regression analysis and ROC curve analysis indicated that a crowding value above 0.13 was a significant (P < 0.05) risk factor for the development of AAC. CONCLUSIONS: Biometric parameters were significantly different between the eyes from the AAC group to the normal group. Ocular crowding value might be a new noncontact screening method to assess the risk of AAC in adults.

Resveratrol ameliorates disorders of mitochondrial biogenesis and dynamics in a rat chronic ocular hypertension model.

AIMS: To explore the roles of mitochondrial biogenesis and dynamics in both RGC-5 cells apoptosis and rat retinal damage induced by elevated pressure and their involvement in resveratrol (RSV)-induced cell protection. MATERIALS AND METHODS: The chronic ocular hypertension (COH) model was established in rats by injecting superparamagnetic iron oxide into anterior chamber. The RGC-5 cells were incubated under ambient and elevated pressure (70 mm Hg) respectively. The intraocular pressure (IOP) was measured using a handheld Tonolab tonometer; mitochondrial dysfunction was analyzed by membrane potential (MMP) depolarization, reactive oxygen species (ROS) level and transmission electron microscope (TEM) detection. Annexin V/PI staining and the terminal deoxynucleotidy transferase dUTP nick end labeling (TUNEL) staining assay were performed for apoptosis detection. Hematoxylin-Eosin staining was performed for retinal morphology detection. The expression of mitochondrial biogenesis and dynamics relating proteins were analyzed by western blot. KEY FINDINGS: The retinal morphology and mitochondrial function deteriorated in chronic ocular hypertension (COH) rats. The cells showed apoptosis and mitochondrial dysfunction under elevated pressure (70 mm Hg) incubation. Upregulating AMPK, NRF-1, Tfam, mfn-2, OPA1 expression with RSV-treatment could decrease the cell apoptosis, mitochondrial membrane potential depolarization, ROS generation both in in vitro and in vivo experiments, and normalized the retinal morphology in vivo. SIGNIFICANCE: Both in vitro and in vivo experiments demonstrated that activated AMPK/PGC-1α signaling pathway and improved expression of proteins were related to mitochondrial dynamics could be the possible mechanism underlying in the RSV's mitochondrial protection.

Biodegradable PTLGA Terpolymers versus Collagen Implants Used as an Adjuvant in Trabeculectomy in Rabbit Eye.

Purpose. To evaluate the effectiveness and safety of three biodegradable terpolymers prepared from L-lactide, trimethylene carbonate, and glycolide (PTLGA) as an aid for trabeculectomy compared with the Ologen (OLO). Methods. Trabeculectomy was carried out on rabbits with implantation made from OLO or three PTLGA terpolymers. Intraocular pressure (IOP) was recorded 1, 2, 3, and 6 months postoperatively and bleb evaluations were performed using ultrasound biomicroscopy (UBM) 3 months after surgery, optical coherence tomography (OCT) every month, and transmission electron microscopy (TEM) six months after surgery followed by histological examination 1, 2, 3, and 6 months postoperatively. Result. IOP was significantly reduced in all groups after surgery. There were no significant differences in the IOL between groups at any time after implantation. There was no significant difference between the groups examined by OCT, UBM, and TEM. Exposure of the implant was observed in one eye from the OLO group and one eye in the P1. Subconjunctiva hyperblastosis was observed in one eye from group P3 and two eyes from the OLO group. Conclusions. Subconjunctival implantation of filtering devices made from PTLGA may present a safe and effective additional surgical tool for the treatment of filtering surgery. Fewer complications were observed in the group with P2 implants compared to other groups.

Analysis of corneal astigmatism in cataract surgery candidates at a teaching hospital in Shanghai, China.

PURPOSE: To describe and quantify the pattern of corneal astigmatism in cataract surgery candidates and to provide information for cataract surgeons and intraocular lens (IOL) manufacturers. SETTING: Zhongshan Hospital, Fudan University, Shanghai, China. DESIGN: Cross-sectional study. METHODS: The datasets of cataract surgery candidates acquired between November 1, 2009, and November 30, 2011, were collected and analyzed. Keratometry values were optically measured by partial coherence interferometry (IOLMaster) before cataract extraction. Spearman rank correlation coefficients were used to estimate bivariate correlations. The power vector method, J(0) and J(45) values, and linear regression models were used to assess the association between age and astigmatism. RESULTS: The study evaluated the keratometry values in 1430 eyes (827 patients) with a median age of 75 years (range 16 to 98 years). The corneal astigmatism was 1.00 diopter (D) or higher in 45.45% of eyes. The magnitude of corneal astigmatism was positively correlated with age (ρ = 0.126, P = .000). A trend toward increasing against-the-rule astigmatism with age was found by linear regression models; the per-year increase in age was associated with a J(0) decrease of 0.016 D in right eyes and 0.018 D in left eyes (both P = .000). No association was found between age and J(45). CONCLUSIONS: Most eyes having corneal astigmatism of 1.00 D or greater could be covered by the range of the cylindrical power of the toric IOLs available on the market. Against-the-rule corneal astigmatism of relatively younger cataract surgery candidates should be managed more aggressively. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Fibroblast growth factor 10 upregulates the expression of mucins in rat conjunctival epithelial cells.

PURPOSE: This in vitro study aimed to gain insight into the function of fibroblast growth factor 10 (FGF10) on the ocular surface, especially its effect on mRNA expression of the mucins Muc1, Muc4, and Muc5ac, and mucin protein synthesis. METHODS: We isolated primary cultured rat conjunctival epithelial cells (Cj-ECs) and treated them with FGF10 (1 ng/ml, 10 ng/ml, 100 ng/ml, and 200 ng/ml) and basic fibroblast growth factor 2 (FGF2; 10 ng/ml) for 24 h or 48 h. The proliferation of Cj-ECs was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). mRNA levels of Muc1, Muc4, and Muc5ac were determined by real-time PCR. Synthesis levels of MUC1 and MUC4 were measured by western blot. Flow cytometry and Annexin V/PI double staining revealed degrees of apoptosis. RESULTS: In primary culture, the epithelial cells were compact and cobblestone pavement in shape. Most of the cells were positive for cytokeratin (CK). FGF10 and FGF2 significantly stimulated Muc1, Muc4, and Muc5ac mRNA expression, cell proliferation, and synthesis of MUC1 and MUC4 proteins. FGF10 was more potent than FGF2 in these regards. FGF10 did not restrain the apoptosis of Cj-ECs. CONCLUSIONS: The results of this study demonstrated that FGF10 is associated with the promotion of Cj-EC proliferation and mucin production. The effects of FGF10 on Cj-ECs support a rationale to investigate its therapeutic potential for ocular surface diseases.

Corneal asphericity and its related factors in 1052 Chinese subjects.

PURPOSE: To observe and analyze corneal asphericity and its related factors in Chinese subjects. METHODS: The corneal asphericity of 1052 right eyes from a Chinese population was determined using the Wavelight-ALLEGRO Topographer. The corneal asphericity coefficient Q describes the rate of curvature variation of the cornea from its center to the periphery and specifies the type of conicoid that best represents its shape. All cases were grouped by age in years (A: ≤ 9; B: 10 to 19; C: 20 to 29; D: 30 to 39; E: 40 to 49; F: ≥50), and 223 myopic cases were grouped by magnitude in spherical equivalent (SE) refractive error (low myopia, > -3.0 diopters (D); moderate myopia, -6.0 D < SE ≤ -3.0 D; high myopia, -8.0 D < SE ≤ -6.0 D; and super high myopia, SE ≤ -8.0 D). In addition, corneal asphericity was analyzed by corneal quadrant (nasal, temporal, superior, and inferior) and two meridians (vertical and horizontal). RESULTS: The mean Q value of 1052 right eyes was -0.30 ± 0.12. Although statistical differences were found between some age groups, no statistical correlation between Q values and age was found in this study (r = -0.58, p = 0.06). Q values of the nasal and superior corneal quadrant were significantly more oblate than that of the temporal and inferior quadrants, respectively (both p < 0.0001). A trend toward more oblate Q values was found as the level of myopia increased (r = 0.166, p = 0.013). There was a negative relationship between Q value and central corneal radius in this entire study population (r = -0.09, p = 0.004). CONCLUSIONS: Corneal asphericity in this population is related more to corneal quadrant location than to age. The results from this study suggest that degree of myopia and central corneal radius both have a significant though weak association with corneal asphericity in Chinese eyes.

Time course of Q value after myopic laser-assisted in situ keratomileusis.

OBJECTIVE: To assess the time course of Q value after myopic laser-assisted in situ keratomileusis (LASIK) and preliminarily evaluate the determinants of the difference of Q value between before and after LASIK. METHODS: We performed a retrospective, longitudinal investigation on patients undergoing wavefront optimized LASIK therapy for emmetropization. A total of 418 eyes from 222 cases were examined preoperatively, and partly followed up at one week (172 eyes), one month (134 eyes) and three months (51 eyes) after surgery. The horizontal, vertical and total Q values of cornea were calculated from eccentricity measured at the central 6-mm corneal zones respectively. Potential determinants of the change of Q value were analyzed using multiple linear regressions. RESULTS: The mean Q value was -0.17 +/- 0.13 preoperatively, and 0.99 +/- 0.70, 0.97 +/- 0.66, and 0.86 +/- 0.41 one week, one and three months postoperatively, respectively. One way analysis of variance (ANOVA) demonstrated significant differences between measurements made before surgery and at all postoperative times (at one week, one and three months; all P<0.0001, Bonferroni post hoc), but no significant differences were found among postoperative groups. Significant differences of Q values between horizontal and vertical meridians were found before surgery and at all postoperative times (all P<0.0001). Multiple regression analysis revealed that change of Q value significantly correlated with manifest refraction spherical equivalent (r=0.116, P<0.0001) and axial length (r=0.264, P<0.0001). CONCLUSIONS: Over the study period, the primary changes in Q value occur within 1 week after surgery, and then become slightly decreased and nearly stable. Manifest refraction spherical equivalent and axial length play a significant role in the change of postoperative Q value.