Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract: a randomized clinical trial.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P<0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P=0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer (P<0.001) than that of the combined group (12.44±6.48d). CONCLUSION: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries.

Impact of Non-Diameter Aortic Indices on Surgical Eligibility: Results from the TITAN: SvS Randomized Controlled Trial.

OBJECTIVES: Traditional criteria for intervention on an asymptomatic ascending aortic aneurysm has been a maximal aortic diameter of ⩾5.5cm. The 2022 ACC/AHA aortic guidelines adopted cross-sectional aortic area/height ratio, aortic size index (ASI) and aortic height index (AHI) as alternate parameters for surgical intervention. The objective of this study was to evaluate the impact of using these newer indices on patient eligibility for surgical intervention in a prospective, multicenter cohort with moderate sized ascending aortic aneurysms between 5.0-5.4 cm. METHODS: Patients enrolled from 2018 to 2023 in the randomization or registry arms of the multicenter trial, TITAN: SvS, were included in the study. Clinical data was captured prospectively in an online database. Imaging data were derived from a core CT lab. RESULTS: Among the 329 included patients, 20% were female. Mean age was 65.0 ± 11.6 years and mean maximal aortic diameter was 50.8 ±3.9 mm. In the one third of all patients (n=109) who met any one of the three criteria (i.e., ASI ⩾ 3.08 cm/m2, AHI ⩾ 3.21 cm/m or cross-sectional aortic area/height ⩾ 10 cm2/m), their mean maximal aortic diameter was 52.5 ±0.52 mm. Alternate criteria were most commonly met in females compared to males: 20% versus 2% for ASI (p<0.001), 39% versus 5% for AHI (p<0.001) and 39% versus 21% for cross-sectional aortic area/height (p=0.002), respectively. CONCLUSIONS: One third of patients in Titan:SvS would meet criteria for surgical intervention based on novel parameters vs. the classic definition of diameter⩾5.5cm. Surgical thresholds for ASI, AHI or cross-sectional aortic area/height ratio are more likely to be met in female patients compared to male patients.

Unraveling Key m6A Modification Regulators Signatures in Postmenopausal Osteoporosis through Bioinformatics and Experimental Verification.

OBJECTIVE: Bone marrow mesenchymal stem cells (BMSCs) show significant potential for osteogenic differentiation. However, the underlying mechanisms of osteogenic capability in osteoporosis-derived BMSCs (OP-BMSCs) remain unclear. This study aims to explore the impact of YTHDF3 (YTH N6-methyladenosine RNA binding protein 3) on the osteogenic traits of OP-BMSCs and identify potential therapeutic targets to boost their bone formation ability. METHODS: We examined microarray datasets (GSE35956 and GSE35958) from the Gene Expression Omnibus (GEO) to identify potential m6A regulators in osteoporosis (OP). Employing differential, protein interaction, and machine learning analyses, we pinpointed critical hub genes linked to OP. We further probed the relationship between these genes and OP using single-cell analysis, immune infiltration assessment, and Mendelian randomization. Our in vivo and in vitro experiments validated the expression and functionality of the key hub gene. RESULTS: Differential analysis revealed seven key hub genes related to OP, with YTHDF3 as a central player, supported by protein interaction analysis and machine learning methodologies. Subsequent single-cell, immune infiltration, and Mendelian randomization studies consistently validated YTHDF3's significant link to osteoporosis. YTHDF3 levels are significantly reduced in femoral head tissue from postmenopausal osteoporosis (PMOP) patients and femoral bone tissue from PMOP mice. Additionally, silencing YTHDF3 in OP-BMSCs substantially impedes their proliferation and differentiation. CONCLUSION: YTHDF3 may be implicated in the pathogenesis of OP by regulating the proliferation and osteogenic differentiation of OP-BMSCs.

Efficacy and safety of Panax notoginseng saponin injection in the treatment of acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

Purpose: This study aimed to assess the efficacy and safety of Panax notoginseng saponin (PNS) injection, when combined with conventional treatment (CT), for acute myocardial infarction (AMI). Methods: Comprehensive searches were conducted in seven databases from inception until 28 September 2023. The search aimed to identify relevant randomized controlled trials (RCTs) focusing on PNS injection in the context of AMI. This meta-analysis adhered to the PRISMA 2020 guidelines, and its protocol was registered with PROSPERO (number: CRD42023480131). Result: Twenty RCTs involving 1,881 patients were included. The meta-analysis revealed that PNS injection, used adjunctively with CT, significantly improved treatment outcomes compared to CT alone, as evidenced by the following points: (1) enhanced total effective rate [OR = 3.09, p < 0.05]; (2) decreased incidence of major adverse cardiac events [OR = 0.32, p < 0.05]; (3) reduction in myocardial infarct size [MD = -6.53, p < 0.05]; (4) lower ST segment elevation amplitude [MD = -0.48, p < 0.05]; (5) mitigated myocardial injury as indicated by decreased levels of creatine kinase isoenzymes [MD = -11.19, p < 0.05], cardiac troponin T [MD = -3.01, p < 0.05], and cardiac troponin I [MD = -10.72, p < 0.05]; (6) enhanced cardiac function, reflected in improved brain natriuretic peptide [MD = -91.57, p < 0.05], left ventricular ejection fraction [MD = 5.91, p < 0.05], left ventricular end-diastolic dimension [MD = -3.08, p < 0.05], and cardiac output [MD = 0.53, p < 0.05]; (7) reduced inflammatory response, as shown by lower levels of C-reactive protein [MD = -2.99, p < 0.05], tumor necrosis factor-α [MD = -6.47, p < 0.05], interleukin-6 [MD = -24.46, p < 0.05], and pentraxin-3 [MD = -2.26, p < 0.05]; (8) improved vascular endothelial function, demonstrated by decreased endothelin-1 [MD = -20.56, p < 0.05] and increased nitric oxide [MD = 1.33, p < 0.05]; (9) alleviated oxidative stress, evidenced by increased superoxide dismutase levels [MD = 25.84, p < 0.05]; (10) no significant difference in adverse events [OR = 1.00, p = 1.00]. Conclusion: This study highlighted the efficacy and safety of adjunctive PNS injections in enhancing AMI patient outcomes beyond CT alone. Future RCTs need to solidify these findings through rigorous methods. Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/), identifier (CRD42023480131).

Granulocyte-Macrophage Colony-Stimulating Factor in Combination With Chemoradiation for Recurrent or Metastatic Cervical Cancer.

Recurrent or metastatic cervical cancer carries a bleak prognosis and presents a formidable challenge in terms of treatment. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the body's immune response by enhancing antigen presentation, which has been rarely reported in recurrent or metastatic cervical cancer. A 44-year-old woman presented to the hospital with vaginal bleeding four years after radical hysterectomy for stage IB2 squamous cell carcinoma (SCC) of the cervix (grade II-III). Gynecological examination and imaging revealed a vaginal mass, and the biopsy confirmed the recurrence of grade III SCC. The patient was treated with chemoradiation (CRT) combined with immunoadjuvant GM-CSF and achieved complete remission and a progression-free survival of two years.

Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4.

Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.

Repeat DNA methylation is modulated by adherens junction signaling.

Through its involvement in gene transcription and heterochromatin formation, DNA methylation regulates how cells interact with their environment. Nevertheless, the extracellular signaling cues that modulate the distribution of this central chromatin modification are largely unclear. DNA methylation is highly abundant at repetitive elements, but its investigation in live cells has been complicated by methodological challenges. Utilizing a CRISPR/dCas9 biosensor that reads DNA methylation of human α-satellite repeats in live cells, we here uncover a signaling pathway linking the chromatin and transcriptional state of repetitive elements to epithelial adherens junction integrity. Specifically, we find that in confluent breast epithelial cell monolayers, α-satellite repeat methylation is reduced by comparison to low density cultures. This is coupled with increased transcriptional activity at repeats. Through comprehensive perturbation experiments, we identify the junctional protein E-cadherin, which links to the actin cytoskeleton, as a central molecular player for signal relay into the nucleus. Furthermore, we find that this pathway is impaired in cancer cells that lack E-cadherin and are not contact-inhibited. This suggests that the molecular connection between cell density and repetitive element methylation could play a role in the maintenance of epithelial tissue homeostasis.

Methyltransferase METTL3-mediated maturation of miR-4654 facilitates high glucose-induced apoptosis and oxidative stress in lens epithelial cells via decreasing SOD2.

N6-methyladenosine (m6 A) modification has been reported to have roles in modulating the development of diabetic cataract (DC). Methyltransferase-like 3 (METTL3) is a critical m6 A methyltransferase involving in m6 A modification activation. Here, we aimed to explore the action and mechanism of METTL3-mediated maturation of miR-4654 in DC progression. Human lens epithelial cells (HLECs) were exposed to high glucose (HG) to imitate DC condition in vitro. Levels of genes and proteins were tested via qRT-PCR and western blotting assays. The proliferation and apoptosis of HLECs were evaluated by cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays, respectively. Oxidative stress was analyzed by detecting the contents of reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). The binding of miR-4654 and SOD2 was confirmed by dual-luciferase reporter assay. The m6 A-RNA immunoprecipitation (MeRIP) assay detected the m6 A modification profile. Thereafter, we found that miR-4654 expression was elevated in DC samples and HG-induced HLECs. MiR-4654 knockdown reversed HG-mediated apoptosis and oxidative stress in HLECs. Mechanistically, miR-4654 directly targeted SOD2, silencing of SOD2 abolished the protective effects of miR-4654 knockdown on HLECs under HG condition. In addition, METTL3 induced miR-4654 maturation through promoting pri-miR-4654 m6 A modification, thereby increasing miR-4654 content in HLECs. METTL3 was highly expressed in DC samples and HG-induced HLECs, METTL3 deficiency protected HLECs against HG-mediated apoptotic and oxidative injury via down-regulating miR-4654. In all, METTL3 induced miR-4654 maturation in a m6 A-dependent manner, which was then reduced SOD2 expression, thus promoting apoptosis and oxidative stress in HLECs, suggesting a novel path for DC therapy.

Bacillus licheniformis ameliorates Aflatoxin B1-induced testicular damage by improving the gut-metabolism-testis axis.

Global aflatoxin B1 (AFB1) contamination is inevitable, and it can significantly damage testicular development. However, the current mechanism is confusing. Here, by integrating the transcriptome, microbiome, and serum metabolome, we comprehensively explain the impact of AFB1 on testis from the gut-metabolism-testis axis. Transcriptome analysis suggested that AFB1 exposure directly causes abnormalities in testicular inflammation-related signalling, such as tumor necrosis factor (TNF) pathway, and proliferation-related signalling pathways, such as phosphatidylinositide 3-kinases-protein kinase B (PI3K-AKT) pathway, which was verified by immunofluorescence. On the other hand, we found that upregulated inflammatory factors in the intestine after AFB1 exposure were associated with intestinal microbial dysbiosis, especially the enrichment of Bacilli, and enrichment analysis showed that this may be related to NLR family pyrin domain containing 3 (NLRP3)-mediated NOD-like receptor signalling. Also, AFB1 exposure caused blood metabolic disturbances, manifested as decreased hormone levels and increased oxidative stress. Significantly, B. licheniformis has remarkable AFB1 degradation efficiency (> 90%). B. licheniformis treatment is effective in attenuating gut-testis axis damage caused by AFB1 exposure through the above-mentioned signalling pathways. In conclusion, our findings indicate that AFB1 exposure disrupts testicular development through the gut-metabolism-testis axis, and B. licheniformis can effectively degrade AFB1.

Structural characterization of the DNA binding mechanism of retinoic acid-related orphan receptor gamma.

Retinoic acid-related orphan receptor gamma (RORγ) plays critical roles in regulating various biological processes and has been linked to immunodeficiency disorders and cancers. DNA recognition is essential for RORγ to exert its functions. However, the underlying mechanism of the DNA binding by RORγ remains unclear. In this study, we present the crystal structure of the complex of RORγ1 DNA-binding domain (RORγ1-DBD)/direct repeat DNA element DR2 at 2.3 Å resolution. We demonstrate that RORγ1-DBD binds the DR2 motif as a homodimer, with the C-terminal extension (CTE) region of RORγ1-DBD contributing to the DNA recognition and the formation of dimeric interface. Further studies reveal that REV-ERB-DBD and RXR-DBD, also bind the DR2 site as a homodimer, while NR4A2-DBD binds DR2 as a monomer. Our research uncovers a binding mechanism of RORγ1 to the DR2 site and provides insights into the biological functions of RORγ1 and the broader RORs subfamily.

Diagnostic value of Procalcitonin, C-reactive protein-to-lymphocyte ratio (CLR), C-reactive protein and neutrophil-to-lymphocyte ratio (NLR) for predicting patients with Bacteraemia in the intensive care unit.

BACKGROUND: To explore the diagnostic value of procalcitonin (PCT), C-reactive protein-to-lymphocyte ratio (CLR), C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) for predicting patients with bacteremia in the intensive care unit (ICU). METHODS: This case-control study included 359 patients with suspected bacteremia were divided into a bacteremia group (n = 152) and a control group (n = 207) from September 2018 to April 2023. Patient data were collected using a laboratory information system (LIS). ROC curves for PCT, CLR, CRP, and NLR in predicting patients with bacteremia. RESULTS: For PCT, CLR, CRP and NLR to predict patients with bacteremia in the ICU, the AUCs were 0.991(95%CI: 0.974-0.998), 0.960(95%CI: 0.935-0.978), 0.955(95%CI: 0.928-0.974), and 0.898(95%CI:0.862-0.927), respectively; the optimal thresholds were 0.248 ng/mL, 47.52 mg/109, 48.32 mg/L, and 6.51, respectively; the sensitivities were 95.4(95%CI: 90.7-98.1), 88.2(95%CI: 81.9-92.8), 87.5(95%CI: 81.2-92.3), and 86.8(95%CI:80.4-91.8), respectively; and the specificities were 95.7(95%CI: 91.9-98.0), 90.8(95%CI: 86.0-94.4), 90.3(95%CI: 85.5-94.0), and 85.0(95%CI:79.4-89.6), respectively. The sensitivities of PCT, CLR, CRP and NLR for predicting bacteremia due to E. coli infection are as high as over 90%, the specificity of PCT is 100, and the sensitivity of NLR is 100. The sensitivity of CRP for predicting bacteremia due to non-Enterobacer infection is 100. CONCLUSIONS: Compared with those in the control group, PCT, CLR, CRP and NLR were significantly greater in the bacteremia group. The PCT, CLR, CRP, and NLR can all predict the occurrence of bacteremia. The PCT had the highest sensitivity and specificity in predicting bacteremia in ICU patients.

Learning Dynamics from Multicellular Graphs with Deep Neural Networks.

The inference of multicellular self-assembly is the central quest of understanding morphogenesis, including embryos, organoids, tumors, and many others. However, it has been tremendously difficult to identify structural features that can indicate multicellular dynamics. Here we propose to harness the predictive power of graph-based deep neural networks (GNN) to discover important graph features that can predict dynamics. To demonstrate, we apply a physically informed GNN (piGNN) to predict the motility of multi-cellular collectives from a snapshot of their positions both in experiments and simulations. We demonstrate that piGNN is capable of navigating through complex graph features of multicellular living systems, which otherwise can not be achieved by classical mechanistic models. With increasing amounts of multicellular data, we propose that collaborative efforts can be made to create a multicellular data bank (MDB) from which it is possible to construct a large multicellular graph model (LMGM) for general-purposed predictions of multicellular organization.

Edge-to-edge with partial band mitral valve repair compared to replacement and undersized restrictive annuloplasty for ischemic mitral regurgitation.

Objective: Evidence supports replacement over repair for ischemic mitral regurgitation due to improved durability; however, the latter often involves an undersized ring annuloplasty that does not include edge-to-edge approximation. The objective of this study was to evaluate the outcomes of replacement, edge-to-edge leaflet approximation with mild-undersized annuloplasty and undersized ring annuloplasty for ischemic mitral regurgitation. Methods: This is a single-center retrospective study of patients undergoing mitral surgery for moderate-severe or greater ischemic mitral regurgitation, between 2004 and 2020, with mild-undersized annuloplasty, mitral valve replacement, or undersized restrictive annuloplasty (undersized ring annuloplasty). The primary outcome was all-cause mortality. Secondary outcomes included first recurrence of mitral regurgitation, heart failure hospitalization, and composite of valve-related events (bleeding, thromboembolism, endocarditis, and mitral valve reoperation). Results: There were 121, 93, and 78 patients in the mitral valve replacement, mild-undersized annuloplasty, and undersized restrictive annuloplasty groups, respectively, with a median follow-up of 3.1, 5.9, and 3.8 years, respectively. Both mitral valve replacement (hazard ratio, 1.87; 95% CI, 1.029-3.415) and undersized restrictive annuloplasty (hazard ratio, 2.73; 95% CI, 1.480-5.061) were associated with worse survival compared with mild-undersized annuloplasty. At 2 years, the rate of mild-moderate mitral regurgitation was greater in the mild-undersized annuloplasty group compared with the mitral valve replacement group (P = .001) but less than in the undersized restrictive annuloplasty group (P = .001). The rate of recurrent moderate or greater mitral regurgitation at 2 years was similar between mild-undersized annuloplasty and mitral valve replacement groups but significantly higher after undersized restrictive annuloplasty (P < .0001). Mitral valve replacement and undersized restrictive annuloplasty were associated with a significant increase in the incidence of first heart failure hospitalization compared with mild-undersized annuloplasty (P < .001 and P = .001, respectively). Mitral valve replacement was associated with an increased incidence of valve-related events compared with mild-undersized annuloplasty (P = .002). Conclusions: Surgical edge-to-edge approximation in addition to a mild-undersizing annuloplasty offers similar durability compared with replacement, with a lower rate of hospitalization for heart failure, and may confer a survival advantage.

Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R.

Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1RT663I. This study not only sheds light on the structural basis governing sulfatinib's FGFR/CSF-1R inhibition, but also provides valuable insights into the rational design of dual- or multi-target FGFR inhibitors with selectivity for CSF-1R and sensitivity to gatekeeper mutations.

Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma.

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+-CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.

Two new alkaloids isolated from Dictamnus dasycarpus Turcz.

Two new quinoline alkaloids (1-2) together with twenty-two known alkaloids (3-24) were isolated and identified from Dictamnus dasycarpus Turcz. Compounds 6-7, 9, 11, 15-16, 19 and 24 were isolated from D. dasycarpus for the first time. The structures of all compounds were characterised by spectroscopic methods (1D, 2D NMR and HRESIMS). The anti-proliferative activity was mediated by the arrest of three human cancer cell lines (SW982, HepG2 and A549) of all the compounds that were evaluated by CCK-8 assay.