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Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.
Bai, W, Liu, D, Cheng, Q, Yang, X, Zhu, L, Qin, L, Fang, J
Translational oncology. 2024;:101850
Abstract
PURPOSE Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce. METHODS A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo. RESULTS As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment. CONCLUSION Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.
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Research progress on ocular complications caused by type 2 diabetes mellitus and the function of tears and blepharons.
Wang, X, Fang, J, Yang, L
Open life sciences. 2024;(1):20220773
Abstract
The purpose of this study was to explore the related research progress of ocular complications (OCs) caused by type 2 diabetes mellitus (T2DM), tear and tarsal function, and the application of deep learning (DL) in the diagnosis of diabetes and OCs caused by it, to provide reference for the prevention and control of OCs in T2DM patients. This study reviewed the pathogenesis and treatment of diabetes retinopathy, keratopathy, dry eye disease, glaucoma, and cataract, analyzed the relationship between OCs and tear function and tarsal function, and discussed the application value of DL in the diagnosis of diabetes and OCs. Diabetes retinopathy is related to hyperglycemia, angiogenic factors, oxidative stress, hypertension, hyperlipidemia, and other factors. The increase in water content in the corneal stroma leads to corneal relaxation, loss of transparency, and elasticity, and can lead to the occurrence of corneal lesions. Dry eye syndrome is related to abnormal stability of the tear film and imbalance in neural and immune regulation. Elevated intraocular pressure, inflammatory reactions, atrophy of the optic nerve head, and damage to optic nerve fibers are the causes of glaucoma. Cataract is a common eye disease in the elderly, which is a visual disorder caused by lens opacity. Oxidative stress is an important factor in the occurrence of cataracts. In clinical practice, blood sugar control, laser therapy, and drug therapy are used to control the above eye complications. The function of tear and tarsal plate will be affected by eye diseases. Retinopathy and dry eye disease caused by diabetes will cause dysfunction of tear and tarsal plate, which will affect the eye function of patients. Furthermore, DL can automatically diagnose and classify eye diseases, automatically analyze fundus images, and accurately diagnose diabetes retinopathy, macular degeneration, and other diseases by analyzing and processing eye images and data. The treatment of T2DM is difficult and prone to OCs, which seriously threatens the normal life of patients. The occurrence of OCs is closely related to abnormal tear and tarsal function. Based on DL, clinical diagnosis and treatment of diabetes and its OCs can be carried out, which has positive application value.
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Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.
Li, X, Peng, X, Li, Y, Wei, S, He, G, Liu, J, Li, X, Yang, S, Li, D, Lin, W, et al
Cell communication and signaling : CCS. 2024;(1):12
Abstract
After undergoing metabolic reprogramming, tumor cells consume additional glutamine to produce amino acids, nucleotides, fatty acids, and other substances to facilitate their unlimited proliferation. As such, the metabolism of glutamine is intricately linked to the survival and progression of cancer cells. Consequently, targeting the glutamine metabolism presents a promising strategy to inhibit growth of tumor cell and cancer development. This review describes glutamine uptake, metabolism, and transport in tumor cells and its pivotal role in biosynthesis of amino acids, fatty acids, nucleotides, and more. Furthermore, we have also summarized the impact of oncogenes like C-MYC, KRAS, HIF, and p53 on the regulation of glutamine metabolism and the mechanisms through which glutamine triggers mTORC1 activation. In addition, role of different anti-cancer agents in targeting glutamine metabolism has been described and their prospective applications are assessed.
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Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial.
Mc Causland, FR, Claggett, BL, Vaduganathan, M, Desai, AS, Jhund, P, de Boer, RA, Docherty, K, Fang, J, Hernandez, AF, Inzucchi, SE, et al
JAMA cardiology. 2023;(1):56-65
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Abstract
IMPORTANCE Sodium-glucose cotransporter 2 inhibitors are known to reduce heart failure events and slow progression of kidney disease among patients with heart failure and a reduced ejection fraction. OBJECTIVE To determine the effect of dapagliflozin on cardiovascular and kidney outcomes and the influence of baseline kidney disease among patients with heart failure and a mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. DESIGN, SETTING, AND PARTICIPANTS This was a prespecified analysis conducted from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This was an international, multicenter trial including patients with ejection fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m2 or higher. INTERVENTIONS Dapagliflozin, 10 mg, per day or placebo. MAIN OUTCOMES AND MEASURES Outcomes assessed were whether baseline kidney function modified the treatment effect on the primary outcome (cardiovascular death or worsening heart failure). Also examined was the treatment effect on the prespecified outcomes of eGFR slope and a post hoc composite kidney outcome (first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m2; end-stage kidney disease; death from kidney causes). RESULTS A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male [56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m2; 3070 patients (49%) had an eGFR less than 60 mL/min/1.73 m2. The effect of dapagliflozin on the primary outcome was not influenced by baseline eGFR category (eGFR ≥60 mL/min/1.73 m2: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00; eGFR 45-<60 mL/min/1.73 m2: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73 m2: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR) follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney composite outcome was low (1.1 events per 100 patient-years) and was not affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However, dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95% CI, 0.1-0.9 mL/min/1.73 m2 per year; P = .01) and from month 1 to 36 (difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m2 per year; P < .001). CONCLUSIONS AND RELEVANCE Results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with heart failure and a mildly reduced or preserved ejection fraction. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low. However, dapagliflozin slowed the rate of decline in eGFR compared with placebo. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03619213.
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ZNF384-Related Fusion Genes in Acute Lymphoblastic Leukemia.
Zhu, L, Bai, W, Cheng, Q, Fang, J
Cancer control : journal of the Moffitt Cancer Center. 2023;:10732748231182787
Abstract
Zinc finger protein 384 (ZNF384) encodes a C2H2-type zinc finger protein that can function as a transcription factor. ZNF384 rearrangement in acute lymphoblastic leukemia (ALL) was first reported in 2002. More than 19 different ZNF384 fusion partners have been detected in ALL. These include E1A-binding protein P300 (EP300), CREB-binding protein (CREBBP), transcription factor 3 (TCF3), TATA-box binding protein associated factor 15 (TAF15), Ewing sarcoma breakpoint region 1 gene (EWSR1), AT-rich interactive domain-containing protein 1B (ARID1B), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2), synergin gamma (SYNRG), clathrin heavy chain (CLTC), bone morphogenic protein 2-inducible kinase (BMP2K), Nipped-B-like protein (NIPBL), A Kinase Anchoring Protein 8 (AKAP8), Chromosome 11 Open Reading Frame 74 (C11orf74), DEAD-Box Helicase 42 (DDX42), ATP Synthase F1 Subunit Gamma (ATP2C1), Euchromatic Histone Lysine Methyltransferase 1 (EHMT1), Testic Expressed 41 (TEX41), etc. Patients diagnosed with ALL harboring ZNF384 rearrangements commonly had a good prognosis. The mechanisms, performance, and features of different ZNF384 rearrangements in acute lymphoblastic leukemia have been well evaluated.
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Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria.
Lv, J, Liu, L, Hao, C, Li, G, Fu, P, Xing, G, Zheng, H, Chen, N, Wang, C, Luo, P, et al
Kidney international reports. 2023;(3):499-506
Abstract
INTRODUCTION To date, no specific therapies have been approved for immunoglobulin A nephropathy (IgAN) treatment. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. METHODS This phase 2 randomized placebo-controlled trial aimed to evaluate the efficacy and safety of telitacicept in patients with IgAN. Participants with an estimated glomerular filtration rate (eGFR) >35 ml/min per 1.73 m2 and proteinuria ≥0.75 g/d despite optimal supportive therapy, were randomized 1:1:1 to receive subcutaneous telitacicept 160 mg, telitacicept 240 mg, or placebo weekly for 24 weeks. The primary end point was the change in 24-hour proteinuria at week 24 from baseline. RESULTS Forty-four participants were randomized into placebo (n = 14), telitacicept 160 mg (n = 16), and telitacicept 240 mg (n = 14) groups. Continuous reductions in serum IgA, IgG, and IgM levels were observed in the telitacicept group. Telitacicept 240 mg therapy reduced mean proteinuria by 49% from baseline (change in proteinuria vs. placebo, 0.88; 95% confidence interval, -1.57 to -0.20; P = 0.013), whereas telitacicept 160 mg reduced it by 25% (-0.29; 95% confidence interval, -0.95 to 0.37; P = 0.389). The eGFR remained stable over time. Adverse events (AEs) were similar in all groups. Treatment-emergent AEs were mild or moderate, and no severe AEs were reported. CONCLUSION Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This effect is indicative of a reduced risk for future kidney disease progression.
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Prescribing patterns and factors associated with sodium-glucose cotransporter-2 inhibitor prescribing in patients with diabetes mellitus and atherosclerotic cardiovascular disease.
Ozaki, AF, Ko, DT, Chong, A, Fang, J, Atzema, CL, Austin, PC, Stukel, TA, Tu, K, Udell, JA, Naimark, D, et al
CMAJ open. 2023;(3):E494-E503
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Abstract
BACKGROUND Sodium-glucose cotransporter-2 (SGLT2) inhibitors are cardioprotective agents in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD). Since little is known about their uptake in atherosclerotic CVD, we examined SGLT2 inhibitor prescribing trends and identified potential disparities in prescribing patterns. METHODS We conducted an observational study using linked population-based health data in Ontario, Canada, from April 2016 to March 2020 of patients aged 65 years or older with concomitant type 2 diabetes and atherosclerotic CVD. To examine prevalent prescribing of SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin), we constructed 4 cross-sectional yearly cohorts from Apr. 1 to Mar. 31 (2016/17, 2017/18, 2018/19 and 2019/20). We estimated prevalent SGLT2 inhibitor prescribing by year and by subgroups, and identified factors associated with SGTL2 inhibitor prescribing using multivariable logistic regression. RESULTS There were 208 303 patients in our overall cohort (median age 74.0 yr [interquartile range 68.0-80.0 yr], 132 196 [63.5%] male). Although SGLT2 inhibitor prescribing increased over time, from 7.0% to 20.1%, statin prescribing was initially 10-fold higher and later threefold higher than SGLT2 inhibitor prescribing. In 2019/20, SGLT2 inhibitor prescribing was roughly 50% lower among those aged 75 years or older than among those younger than 75 years (12.9% v. 28.3%, p < 0.001) and in women than in men (15.3% v. 22.9%, p < 0.001). Age 75 years or older, female sex, history of heart failure and kidney disease, and low income were independent factors of lower SGLT2 inhibitor prescribing. Among physician specialists, visits to endocrinologists and family physicians were stronger factors of SGLT2 inhibitor prescribing than cardiologist visits. INTERPRETATION We found that 1 in 5 patients with diabetes and atherosclerotic CVD were prescribed SGLT2 inhibitors in 2019/20, whereas statins were prescribed for 4 of every 5 patients. Although SGLT2 inhibitor prescribing increased over the study period, disparities in adoption by age, sex, socioeconomic status, comorbidities and physician specialty remained.
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The Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Anthracycline-Treated Patients With Cancer.
Abdel-Qadir, H, Carrasco, R, Austin, PC, Chen, Y, Zhou, L, Fang, J, Su, HMH, Lega, IC, Kaul, P, Neilan, TG, et al
JACC. CardioOncology. 2023;(3):318-328
Abstract
BACKGROUND Sodium glucose cotransporter-2 inhibitors (SGLT2is) are hypothesized to reduce the risk of anthracycline-associated cardiotoxicity. OBJECTIVES This study sought to determine the association between SGLT2is and cardiovascular disease (CVD) after anthracycline-containing chemotherapy. METHODS Using administrative data sets, we conducted a population-based cohort study of people >65 years of age with treated diabetes and no prior heart failure (HF) who received anthracyclines between January 1, 2016, and December 31, 2019. After estimating propensity scores for SGLT2i use, the average treatment effects for the treated weights were used to reduce baseline differences between SGLT2i-exposed and -unexposed controls. The outcomes were hospitalization for HF, incident HF diagnoses (in- or out-of-hospital), and documentation of any CVD in future hospitalizations. Death was treated as a competing risk. Cause-specific HRs for each outcome were determined for SGLT2i-treated people relative to unexposed controls. RESULTS We studied 933 patients (median age 71.0 years, 62.2% female), 99 of whom were SGLT2i treated. During a median follow-up of 1.6 years, there were 31 hospitalizations for HF (0 in the SGLT2i group), 93 new HF diagnoses, and 74 hospitalizations with documented CVD. Relative to controls, SGLT2i exposure was associated with HR of 0 for HF hospitalization (P < 0.001) but no significant difference in incident HF diagnosis (HR: 0.55; 95% CI: 0.23-1.31; P = 0.18) or CVD diagnosis (HR: 0.39; 95% CI: 0.12-1.28; P = 0.12). There was no significant difference in mortality (HR: 0.63; 95% CI: 0.36-1.11; P = 0.11). CONCLUSIONS SGLT2is may reduce the rate of HF hospitalization after anthracycline-containing chemotherapy. This hypothesis warrants further testing in randomized controlled trials.
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Research progress on the pathogenesis of diabetic retinopathy.
Li, H, Liu, X, Zhong, H, Fang, J, Li, X, Shi, R, Yu, Q
BMC ophthalmology. 2023;(1):372
Abstract
Diabetic retinopathy is one of the most common and serious microvascular complications of diabetes mellitus. There are many factors leading to diabetic retinopathy, and its pathogenesis is still unclear. At present, there are still no effective measures for the early treatment of diabetic retinopathy, and the treatment options available when diabetes progresses to advanced stages are very limited, and the treatment results are often unsatisfactory. Detailed studies on the molecular mechanisms of diabetic retinopathy pathogenesis and the development of new therapeutic agents are of great importance. This review describes the potential pathogenesis of diabetic retinopathy for experimental studies and clinical practice.
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Crosstalk between autophagy and CSCs: molecular mechanisms and translational implications.
Li, D, Peng, X, He, G, Liu, J, Li, X, Lin, W, Fang, J, Li, X, Yang, S, Yang, L, et al
Cell death & disease. 2023;(7):409
Abstract
Cancer stem cells(CSCs) play a key role in regulating tumorigenesis, progression, as well as recurrence, and possess typical metabolic characteristics. Autophagy is a catabolic process that can aid cells to survive under stressful conditions such as nutrient deficiency and hypoxia. Although the role of autophagy in cancer cells has been extensively studied, CSCs possess unique stemness, and their potential relationship with autophagy has not been fully analyzed. This study summarizes the possible role of autophagy in the renewal, proliferation, differentiation, survival, metastasis, invasion, and treatment resistance of CSCs. It has been found that autophagy can contribute to the maintenance of CSC stemness, facilitate the tumor cells adapt to changes in the microenvironment, and promote tumor survival, whereas in some other cases autophagy acts as an important process involved in the deprivation of CSC stemness thus leading to tumor death. Mitophagy, which has emerged as another popular research area in recent years, has a great scope when explored together with stem cells. In this study, we have aimed to elaborate on the mechanism of action of autophagy in regulating the functions of CSCs to provide deeper insights for future cancer treatment.