Dynamic evolution of bone marrow adipocyte in B cell acute lymphoblastic leukemia: insights from diagnosis to post-chemotherapy.

Adipocyte is a unique and versatile component of bone marrow microenvironment (BMM). However, the dynamic evolution of Bone Marrow (BM) adipocytes from the diagnosis of B cell Acute Lymphoblastic Leukemia (B-ALL) to the post-treatment state, and how they affect the progression of leukemia, remains inadequately explicated. Primary patient-derived xenograft models (PDXs) and stromal cell co-culture system are employed in this study. We show that the dynamic evolution of BM adipocytes from initial diagnosis of B-ALL to the post-chemotherapy phase, transitioning from cellular depletion in the initial leukemia niche to a fully restored state upon remission. Increased BM adipocytes retards engraftment of B-ALL cells in PDX models and inhibits cells growth of B-ALL in vitro. Mechanistically, the proliferation arrest of B-ALL cells in the context of adipocytes-enrichment niche, might attribute to the presence of adiponectin secreted by adipocytes themselves and the absence of cytokines secreted by mesenchymal stem cell (MSCs). In summary, our findings offer a novel perspective for further in-depth understanding of the dynamic balance between BMM and B-ALL.

Impact of measurable residual disease in combination with CD19 on postremission therapy choices for adult t(8;21) acute myeloid leukemia in first complete remission.

BACKGROUND: The post-remission therapy (PRT) choices for adult t(8;21) acute myeloid leukemia (AML) in first complete remission (CR1) need to be further explored. AIMS: We aimed to investigate the impact of measurable residual disease (MRD) combined with CD19 on PRT choices for adult t(8;21) AML in CR1. METHODS: A total of 150 t(8;21) AML patients were enrolled, including 67 underwent chemotherapy (CMT) and 83 allogeneic hematopoietic stem cell transplantation (allo-SCT) as PRT in CR1. Subgroup analyses were performed according to MRD level after three cycles of chemotherapy combined with CD19 expression. RESULTS: Multivariate analysis indicated MRDhigh after three courses of treatment (HR, 0.14 [95% CI, 0.03-0.66]; p = 0.013) and CD19 negativity (HR, 0.14 [95% CI, 0.02-0.96]; p = 0.045) were risk factors for relapse, while allo-SCT was protective factor for relapse (HR, 0.34 [95% CI, 0.15-0.75]; p = 0.008). Grouped by MRD after three courses of chemotherapy, allo-SCT had lower CIR (p < 0.001) and better OS (p = 0.003) than CMT for MRDhigh patients, CMT showed a higher CIR (35.99% vs. 15.34%, p = 0.100) but comparable OS (p = 0.588) than allo-SCT for MRDlow patients. Grouped by CD19 expression, allo-SCT demonstrated lower CIR (p < 0.001) and better OS (p = 0.002) than CMT for CD19- patients. CMT had a higher CIR (41.37% vs. 10.48%, p = 0.007) but comparable OS (p = 0.147) than allo-SCT for CD19+ patients. Grouped by MRD combined with CD19, MRDhigh /CD19+ subsets were identified out of CD19+ patients benefiting from allo-SCT with lower CIR (p = 0.002) and superior OS (p = 0.020) than CMT. CMT preserved comparable CIR (p = 0.939) and OS (p = 0.658) with allo-SCT for MRDlow /CD19+ patients. MRDlow /CD19- subsets were also identified from MRDlow patients requiring allo-SCT with lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT. Allo-SCT maintained lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT for MRDhigh /CD19- patients. CONCLUSIONS: MRD combined with CD19 might optimize PRT choices for adult t(8;21) AML patients in CR1.

Single-cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell-type-specific mechanisms.

High myopia is a leading cause of blindness worldwide with increasing prevalence. Retina percepts visual information and triggers myopia development, but the underlying etiology is not fully understood because of cellular heterogeneity. In this study, single-cell RNA sequencing analysis was performed on retinas of mouse highly myopic and control eyes to dissect the involvement of each cell type during high myopia progression. For highly myopic photoreceptors, Hk2 inhibition underlying metabolic remodeling from aerobic glycolysis toward oxidative phosphorylation and excessive oxidative stress was identified. Importantly, a novel Apoe + rod subpopulation was specifically identified in highly myopic retina. In retinal neurons of highly myopic eyes, neurodegeneration was generally discovered, and the imbalanced ON/OFF signaling driven by cone-bipolar cells and the downregulated dopamine receptors in amacrine cells were among the most predominant findings, indicating the aberrant light processing in highly myopic eyes. Besides, microglia exhibited elevated expression of cytokines and TGF-ß receptors, suggesting enhanced responses to inflammation and the growth-promoting states involved in high myopia progression. Furthermore, cell-cell communication network revealed attenuated neuronal interactions and increased glial/vascular interactions in highly myopic retinas. In conclusion, this study outlines the transcriptional landscape of highly myopic retina, providing novel insights into high myopia development and prevention.

The Zhu-Lu formula: a machine learning-based intraocular lens power calculation formula for highly myopic eyes.

BACKGROUND: To develop a novel machine learning-based intraocular lens (IOL) power calculation formula for highly myopic eyes. METHODS: A total of 1828 eyes (from 1828 highly myopic patients) undergoing cataract surgery in our hospital were used as the internal dataset, and 151 eyes from 151 highly myopic patients from two other hospitals were used as external test dataset. The Zhu-Lu formula was developed based on the eXtreme Gradient Boosting and the support vector regression algorithms. Its accuracy was compared in the internal and external test datasets with the Barrett Universal II (BUII), Emmetropia Verifying Optical (EVO) 2.0, Kane, Pearl-DGS and Radial Basis Function (RBF) 3.0 formulas. RESULTS: In the internal test dataset, the Zhu-Lu, RBF 3.0 and BUII ranked top three from low to high taking into account standard deviations (SDs) of prediction errors (PEs). The Zhu-Lu and RBF 3.0 showed significantly lower median absolute errors (MedAEs) than the other formulas (all P < 0.05). In the external test dataset, the Zhu-Lu, Kane and EVO 2.0 ranked top three from low to high considering SDs of PEs. The Zhu-Lu formula showed a comparable MedAE with BUII and EVO 2.0 but significantly lower than Kane, Pearl-DGS and RBF 3.0 (all P < 0.05). The Zhu-Lu formula ranked first regarding the percentages of eyes within ± 0.50 D of the PE in both test datasets (internal: 80.61%; external: 72.85%). In the axial length subgroup analysis, the PE of the Zhu-Lu stayed stably close to zero in all subgroups. CONCLUSIONS: The novel IOL power calculation formula for highly myopic eyes demonstrated improved and stable predictive accuracy compared with other artificial intelligence-based formulas.

LONG-TERM PROGRESSION PATTERN OF MYOPIC TRACTIONAL MACULOPATHY: Outcomes and Risk Factors.

PURPOSE: To evaluate the long-term progression pattern of myopic tractional maculopathy and the risk factors. METHODS: The prevalence and grade of myopic tractional maculopathy were assessed with optical coherence tomography at enrollment and at the 2-year follow-up. The severity of posterior staphyloma and the presence of dome-shaped macula were also evaluated. RESULTS: In total, 610 highly myopic eyes of 610 patients were analyzed. The prevalence of epiretinal membrane, myopic retinoschisis, and macular hole increased from 26.7%, 12.1%, and 4.4% at enrollment to 41.1%, 18.2%, and 9.5% at the 2-year follow-up, respectively. Epiretinal membrane progressed in 21.8% of eyes, but visual acuity did not decline significantly in these eyes. Myopic retinoschisis progressed in 6.8% of eyes, and macular hole progressed in 14.8% of eyes. Significantly greater best-corrected visual acuity reduction was detected in the eyes with myopic retinoschisis or macular hole progression than the rest ( P < 0.05). Multivariate analysis showed that longer axial length, more-severe posterior staphyloma, and absence of dome-shaped macula were associated with myopic tractional maculopathy progression. CONCLUSION: In highly myopic eyes, long-term visual acuity was relatively stable in those with epiretinal membrane, but was significantly affected by myopic retinoschisis or macular hole progression. Longer axial length, more-severe posterior staphyloma, and absence of dome-shaped macula were risk factors for myopic tractional maculopathy progression.

Single-cell RNA sequencing: Inhibited Notch2 signalling underlying the increased lens fibre cells differentiation in high myopia.

High myopia is the leading cause of blindness worldwide. It promotes the overgrowth of lens, which is an important component of ocular refractive system, and increases the risks of lens surgery. While postnatal growth of lens is based on the addition of lens fibre cells (LFCs) supplemented by proliferation and differentiation of lens epithelial cells (LECs), it remains unknown how these cellular processes change in highly myopic eyes and what signalling pathways may be involved. Single-cell RNA sequencing was performed and a total of 50,375 single cells isolated from the lens epithelium of mouse highly myopic and control eyes were analysed to uncover their underlying transcriptome atlas. The proportion of LFCs was significantly higher in highly myopic eyes. Meanwhile, Notch2 signalling was inhibited during lineage differentiation trajectory towards LFCs, while Notch2 predominant LEC cluster was significantly reduced in highly myopic eyes. In consistence, Notch2 was the top down-regulated gene identified in highly myopic lens epithelium. Further validation experiments confirmed NOTCH2 downregulation in the lens epithelium of human and mouse highly myopic eyes. In addition, NOTCH2 knockdown in primary human and mouse LECs resulted in enhanced differentiation towards LFCs accompanied by up-regulation of MAF and CDKN1C. These findings indicated an essential role of NOTCH2 inhibition in lens overgrowth of highly myopic eyes, suggesting a therapeutic target for future interventions.

The influence of corneal ablation patterns on prediction error after cataract surgery in post-myopic-LASIK eyes.

PURPOSE: To evaluate the influence of corneal ablation patterns on the prediction error after cataract surgery in post-myopic-LASIK eyes. METHODS: Eighty-three post-myopic-LASIK eyes of 83 patients that underwent uneventful cataract surgery were retrospectively included. Predicted postoperative spherical equivalence (SE) was calculated for the implanted lens using the Haigis-L and Barrett True-K formula. Prediction error at one month postsurgery was calculated as actual SE minus predicted SE. For each eye, area and decentration of the ablation zone was measured using the tangential curvature map. The associations between prediction errors and corneal ablation patterns were investigated. RESULTS: The mean prediction error was - 0.83 ± 1.00 D with the Haigis-L formula and - 1.00 ± 0.99 D with the Barrett True-K formula. Prediction error was positively correlated with keratometry (K) value and negatively correlated with ablation zone area using either formula, and negatively correlated with decentration of the ablation zone using the Barrett True-K formula (all P < 0.05). In the K < 37.08 D group, prediction error was negatively correlated with decentration of the ablation zone with both formulas (all P < 0.05). Multivariate analysis showed that with the Haigis-L formula, prediction error was associated with axial length (AL), K value and decentration, and with the Barrett True-K formula, prediction error was associated with AL and decentration (all P < 0.05). CONCLUSION: A flatter cornea, larger corneal ablation zone and greater decentration will lead to more myopic prediction error after cataract surgery in post-myopic-LASIK eyes.

Associations between anterior segment parameters and rotational stability of a plate-haptic toric intraocular lens.

PURPOSE: To evaluate the associations between anterior segment parameters and the rotational stability of a plate-haptic toric intraocular lens (IOL). SETTING: Eye and Ear, Nose, Throat Hospital of Fudan University. DESIGN: Retrospective case series. METHODS: Patients who underwent uneventful phacoemulsification and plate-haptic toric IOL (AT TORBI 709M IOL) implantation were included. Preoperative axial length (AL) and anterior segment parameters, including the white-to-white (WTW) distance, anterior chamber depth (ACD), lens thickness (LT), and anterior segment length (ASL; the sum of ACD and LT) were recorded. IOL rotation, residual astigmatism (RAS), and visual acuity were evaluated 1 month postoperatively. The associations between the anterior segment parameters and IOL rotation were evaluated. RESULTS: A total of 102 eyes of 102 patients were included. The mean AL was 26.43 ± 2.65 mm (range 21.71-34.60 mm). The mean IOL rotation was 4.59 ± 3.18 degrees, and RAS was 0.62 ± 0.39 D postoperatively. No correlation was detected between AL, ACD, or LT and the rotation of the plate-haptic toric IOL (all P > .05). However, its rotation correlated positively with the WTW distance (r = 0.250, P = .011) and ASL (r = 0.214, P = .030). Backward stepwise multiple linear regression revealed that the WTW distance (ß = 2.142, P = .014) and ASL (ß = 2.060, P = .037) were independent predictors of plate-haptic toric IOL rotation. CONCLUSIONS: Plate-haptic toric IOLs rotate more in eyes with larger WTW distances and longer ASLs; therefore, toric IOL implantation should be performed with caution in eyes with these characteristics.

Efficacy and complications of cataract surgery in high myopia.

To evaluate the efficacy and complications of cataract surgery in high myopia, a comprehensive search query was conducted from January 2000 to August 2020. A total of 19 586 highly myopic eyes from 28 studies were included. Modern cataract surgery turns out efficacious in highly myopic eyes with significant improvement of visual acuity. However, phacoemulsification-related complications such as posterior capsular rupture (3.91%, 95% CI, 1.98%-6.37%), retinal detachment (1.74%, 95% CI, 1.36%-2.15%), progressed myopic traction maculopathy (5.07%, 95% CI, 1.80%-9.37%), capsular contraction syndrome (2.1%), intraocular lens dislocation (0.58%), and transient intraocular pressure elevation (28.15%, 95% CI, 20.29%-36.70%) occurred more frequently in the highly myopic population. Separate analyses were also conducted based on follow-up period. In conclusion, modern cataract surgery was effective for highly myopic cataract patients, whereas careful precautions and sufficient follow-ups were of great value because of higher incidences of intraoperative and postoperative complications.

Creatine kinase in the diagnosis and prognostic prediction of amyotrophic lateral sclerosis: a retrospective case-control study.

Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015.

Clinical Characteristics and Early Visual Outcomes of Highly Myopic Cataract Eyes: The Shanghai High Myopia Study.

Purpose: To report ocular characteristics and early visual outcomes of highly myopic cataract eyes, and to analyze the risk factors of low vision. Methods: A total of 2,027 eyes of 1,400 cataract patients with axial length (AL) ≥ 26 mm undergoing cataract surgery in Eye & ENT Hospital of Fudan University, who were registered in the Shanghai High Myopia Study, were analyzed. Routine pre-operative ophthalmic examinations were performed and macular scan of optical coherence tomography (OCT) were obtained. Macular complications, central foveal thickness (CFT) and subfoveal choroidal thickness (SFCT) were evaluated from OCT images. Ocular and surgical history and perioperative complications were also recorded. Uncorrected and best-corrected visual acuity (UCVA/BCVA) 1 month post-operatively and its influencing factors were evaluated. Results: The average AL of all involved eyes was 29.52 ± 2.26 mm, and 39.7% of which were with an AL > 30 mm and 26.4% of which were with a corneal astigmatism more than 1.5 D. Nuclear cataract accounted for the largest proportion (70.6%). The rate of overall macular complications was 27.6%. Postoperative UCVA and BCVA were 0.70 ± 0.46 and 0.25 ± 0.32 logMAR, respectively. BCVA improved significantly after surgery (vs. P < 0.001) and affected by the elongation of AL (P < 0.001) and thinning of CFT and SFCT (both P < 0.001). The risk factors of post-operative low vision (BCVA < 20/66) were macular atrophy, lamellar macular hole, high corneal astigmatism, long AL, thin SFCT and junior surgeons, odds ratios ranging from 1.54 to 54.87 (all P < 0.05). Conclusion: Cataract surgery could improve the VA of highly myopic eyes. Eye with macular complications, higher corneal astigmatism, longer AL, thinner SFCT, and who was treated by a junior surgeon, may have a high risk of low vision after surgery.

Intraoperative Pain Sensation During Cataract Surgery: Why Does Timing Matter?

Purpose: To investigate whether timing influences pain perception during cataract surgery and to investigate the possible mechanisms.Methods: Patients scheduled for cataract surgery both in the morning and afternoon were consecutively enrolled. Questionnaires to evaluate anxiety, including the Simplified State-Trait Anxiety Inventory, Amsterdam Preoperative Anxiety and Information Scale, and a visual analogue scale (VAS) for anxiety, were completed preoperatively, whereas a VAS for pain and the Wong-Baker FACES® Pain Rating Scale questionnaire were completed after surgery. Preoperative blood pressure and heart rate were recorded. Blood samples were acquired before surgery, and plasma cortisol, adrenocorticotropic hormone, adrenalin, and noradrenalin were tested.Results: Fifty-five patients underwent uneverntful cataract surgery (28 in the morning and 27 in the afternoon) were included in the final analysis. Greater intraoperative pain perception during cataract surgery was reported in the afternoon than in the morning. Overall anxiety levels were significantly higher in the afternoon. Plasma adrenalin levels were significantly higher in the afternoon. Cortisol levels were higher in the afternoon. Preoperative anxiety levels were closely related to intraoperative pain perception. Both adrenalin and cortisol correlated positively with preoperative anxiety, but only adrenalin correlated significantly with the pain scores.Conclusions: Patients undergoing cataract surgery in the afternoon showed more preoperative anxiety, which may have increased their relevant stress hormones. Both the patient's emotional state and hormone levels may together aggravate his/her perceived pain in the afternoon. Monitoring preoperative anxiety levels, blood pressure, and heart rate should help to identify patients at higher risk of perceived intraoperative pain.Clinical trial registration:Trial registration number: NCT02182921Registration site: clinicaltrials.gov.

Distribution of angle α and angle κ in a population with cataract in Shanghai.

PURPOSE: To describe the distribution of angle α and angle κ in a population with cataract in Shanghai. SETTING: Eye and Ear, Nose, Throat Hospital, Fudan University, Shanghai, China. DESIGN: Hospital-based, cross-sectional study. METHODS: Angle α, angle κ, and other ocular biometric parameters were determined by IOLMaster 700. The distributions of angle α and angle κ and their associations with systemic and ocular parameters were assessed. RESULTS: This study included 15 127 eyes of 15 127 cataract patients. The mean angle α and angle κ values were 0.45 ± 0.21 mm and 0.30 ± 0.18 mm, respectively. Angle α and angle κ were both predominantly located temporal to the visual axis. A greater angle α or angle κ was associated with older age, lower corneal power, shorter white-to-white distance, and shallower anterior chamber depth (all P < .05). Angle α correlated positively with angle κ. With increasing axial length (AL), angle α gradually decreased in a nonlinear way and shifted to the nasal side of the visual axis, whereas angle κ decreased in eyes with AL less than 27.5 mm but increased again in eyes with longer AL. CONCLUSIONS: Angle α and angle κ, both predominantly located temporal to the visual axis, were influenced by multiple anterior segment parameters. As AL increased, the changes in angle α and angle κ were nonlinear, and their locations gradually shifted from the temporal to the nasal side of the visual axis.

Contrast-Enhanced CT-based Textural Parameters as Potential Prognostic Factors of Survival for Colorectal Cancer Patients Receiving Targeted Therapy.

PURPOSE: This study was designed to estimate the clinical significance of the contrast-enhanced computed tomography (CT) textural features for prediction of survival in colorectal cancer (CRC) patients receiving targeted therapy (bevacizumab and cetuximab). PROCEDURES: The LifeX software was used to extract the textural parameters of the tumor lesions in the contrast-enhanced CT. We used the least absolute shrinkage and selection operator (LASSO) Cox regression and random forest method to screen the non-redundant radiomic features and constructed the CT imaging score. Univariate and multivariate analyses through the Cox proportional hazards model were performed to assess the prognostic clinical factor. Based on the result of multivariate analysis and CT imaging score, combined nomogram model was constructed to predict the overall survival (OS) of patients. Decision curves analysis was employed to evaluate the performance of the combined model and clinical model. RESULTS: After comparative analysis of the area under curve of the receiver operating characteristic (ROC) curve, we chose the result of random forest model as CT imaging score. Considering the clinical practice and the result of analysis, age, surgery, and lactate dehydrogenase (LDH) level have been introduced into clinical model. Based on the result of analysis and the CT imaging score, we constructed the nomogram combined model. C-index and calibration curve verified the goodness of fit and discrimination of the combined model. Decision curve analysis (DCA) demonstrated that the combined model showed the better net benefit for a 3-year OS than clinical model. CONCLUSIONS: In conclusion, the study provides preliminary evidences that several radiomic parameters of tumor lesions derived from CT images were prognostic factors and predictive markers for CRC patients who are candidates for targeted therapy (bevacizumab and cetuximab).