Radiotherapy enhances efficacy of PD-1 inhibitors in advanced hepatocellular carcinoma: A propensity-matched real-world study.

BACKGROUND: To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma (HCC), combination with radiotherapy (RT) has emerged as a promising strategy. In preclinical studies, irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy. Hence, we investigated whether RT enhances the efficacy of anti-programmed death receptor-1 (PD-1) inhibitors in advanced HCC in real-world practice. METHODS: Between August 2018 and June 2021, 172 patients with advanced primary HCC were enrolled in the tertiary center (Zhongshan Hospital of Fudan University); 95 were treated with a combination of RT and the inhibitor of PD-1 (RT-PD1 cohort), and 77 were administered anti-PD-1 therapy (PD1 cohort). The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT. Propensity score matching for bias reduction was used to evaluate the clinical outcomes. RESULTS: Among 71 propensity-matched pairs, median progression-free survival was 5.7 months in the RT-PD1 cohort vs. 2.9 months in the PD1 cohort (P <0.001). Median overall survival was 20.9 months in the RT-PD1 cohort vs. 11.2 months in the PD1 cohort (P = 0.018). Compared with patients in the PD1 cohort, patients in the RT-PD1 cohort had significantly higher objective response rates (29/71, 40.8% vs. 14/71, 19.7%, P = 0.006) and disease control rates (44/71, 62.0% vs. 22/71, 31.0%, P <0.001). The incidences of toxic effects were not significantly different between the two cohorts. CONCLUSIONS: RT plus anti-PD-1 therapy is well tolerated. RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.

Localized light chain amyloidosis involving the lacrimal sac: A case report.

Amyloidosis involving the lacrimal sac is extremely rare. In this study, we demonstrated a rare case of localized light chain amyloidosis in the lacrimal sac region. The lacrimal sac lesion presented as infiltrative with bony erosion. Given the slow growth of the lesion and the absence of a blood flow signal inside, we concluded that the lesion was less likely to be malignant. Complete removal of the lacrimal sac lesion combined with simultaneous lacrimal passage reconstruction was performed. The diagnosis of light chain amyloidosis was confirmed by histology. The surgical results were favorable, and no recurrence was observed over one-year follow-up. Our case report enriches the understanding of amyloid deposition in the ocular adnexa.

Development and Validation of a Nomogram for Patients Undergoing Transarterial Chemoembolization for Recurrent Hepatocellular Carcinoma After Hepatectomy.

Purpose: This study aims to establish a prognostic nomogram for patients who underwent transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (HCC) after hepatectomy. Patients and Methods: Patients who underwent TACE for recurrent early- and middle-stage HCC after hepatectomy between 2009.01 and 2015.12 were included. Enrolled patients were randomly divided into training (n=345) and validation (n=173) cohorts according to a computer-generated randomized number. Independent factors for overall survival (OS) were determined and included in the nomogram based on the univariate and multivariate analyses of the training group. The nomogram was validated and compared to other prognostic models. Discriminative ability and predictive accuracy were determined using the Harrell C index (C-index), area under the receiver operating characteristic curve (AUROC), and calibration curve. Results: The final nomogram was established based on four parameters including resection-to-TACE time interval, recurrent tumor diameter, recurrent tumor number, and AFP level. The C-indexes of the nomogram for predicting OS were 0.67 (95% CI 0.63-0.70) and 0.71 (95% CI 0.68-0.74) in the training and validation cohort respectively. The AUROCs for predicting the 1-year, 2-year and 3-year OS based on the nomogram were also superior to those of the other models. The calibration curve for 3-year survival showed a high congruence between the predicted and actual survival probabilities. According to the scores calculated by the nomogram, patients were stratified into three subgroups: high-risk (scoring ≥53 points), middle-risk (scoring ≥26 and <53 points), and low-risk (scoring <26 points) subgroups with a median OS of 10.1 (95% CI 0.63-0.70), 20.3 (95% CI 17.5-22.5) and 47.0 (95% CI 34.2-59.8) months, respectively. Conclusion: The proposed nomogram served as a new tool to predict individual survival in patients who underwent TACE for recurrent HCC after hepatectomy, with favorable performance and discrimination. For high-risk patients, treatment should be optimized beyond TACE alone based on the nomogram.

Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy for hepatocellular carcinoma patients with portal vein tumor thrombus.

Background: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) present a poor prognosis. Current systemic therapies offer limited benefits. Hepatic artery infusion chemotherapy (HAIC) is a local regional treatment for advanced HCC, particularly in selected patients such as patients with PVTT or high intrahepatic tumor burden. Objectives: The purpose of this study is to retrospectively evaluate the efficacy and safety of HAIC combined with anti-PD-1 immunotherapy for HCC patients with PVTT, and explore factors related to survival prognosis, providing clues for treatment decisions for HCC patients. Design: This is a single-center retrospective study conducted over 2 years on consecutive PVTT patients receiving HAIC combined anti-PD-1 antibodies. Methods: The primary endpoint was overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors affecting OS. Treatment-associated adverse events were evaluated as well. Results: A total of 119 patients were analyzed. The median OS and PFS were 14.9 months and 6.9 months. A total of 31.1% of grade 3-4 adverse events were reported, with elevated transaminase and total bilirubin being the most common. The independent variables correlated with survival include treatment-related alpha-fetoprotein (AFP) response, the presence of extrahepatic organ metastasis, absolute value of platelet (PLT), neutrophil-to-lymphocyte ratio, and combined usage of tyrosine kinase inhibitors (TKIs). Conclusion: In HCC patients with PVTT, combination therapy with HAIC and anti-PD-1 antibodies might be a promising therapy. The efficacy and safety of this combination protocol on patients with HCC complicated by PVTT warrants further investigation prospectively, especially in combination with TKIs.

CT-Measured Angulation Between the Frontal Bone and Bony Nasolacrimal Duct: Variations in Obstructed and Healthy Lacrimal Ducts.

PURPOSE: The aim of this study was to analyze the characteristics of CT-measured intersection angle (FB-BNLD) between the frontal bone and bony nasolacrimal duct and to provide suggestions for treating primary acquired nasolacrimal duct obstruction (PANDO) patients in West China. METHODS: Three hundred and nine participants' CT were, respectively, evaluated with RadiAnt DICOM Viewer. We defined the FB-BNLD angle >0° as the anterior type and the FB-BNLD angle ≤0° as the posterior type. RESULTS: The mean FB-BNLD was -2.52° (95% CI, -3.16° to -1.88°) across all participants, of whom 37.2% were of the anterior type and 62.8% of the posterior type. Approximately 65.0% of the female patients had a posterior FB-BNLD type, and 54.2% of the male patients had an anterior FB-BNLD type (p = .002). Posterior FB-BNLD was the dominant type in the PANDO and control groups (p = .011), and the angle of FB-BNLD was statistically different in both groups (PANDO group, -2.54° to -0.71°; control group, -4.42° to -2.67°; p < .001). Among the male participants, the type of FB-BNLD differed between the two groups (p = .036), with differences in the angle of FB-BNLD (PANDO group, 0.59° to 5.13°; control group, -4.08° to 1.89°; p = .034). There was no difference in the type of FB-BNLD in female participants between the two groups (p = .051). CONCLUSION: The present study revealed individual differences in the type of FB-BNLD, with anterior-type majority in males and posterior-type dominance in females. Evaluating the FB-BNLD type on CT can provide a fast method for knowing the nasolacrimal duct condition during planning for lacrimal manipulation.

Development and Preliminary Validation of a Novel Convolutional Neural Network Model for Predicting Treatment Response in Patients with Unresectable Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy.

The goal of this study was to evaluate the performance of a convolutional neural network (CNN) with preoperative MRI and clinical factors in predicting the treatment response of unresectable hepatocellular carcinoma (HCC) patients receiving hepatic arterial infusion chemotherapy (HAIC). A total of 191 patients with unresectable HCC who underwent HAIC in our hospital between May 2019 and March 2022 were retrospectively recruited. We selected InceptionV4 from three representative CNN models, AlexNet, ResNet, and InceptionV4, according to the cross-entropy loss (CEL). We subsequently developed InceptionV4 to fuse the information from qualified pretreatment MRI data and patient clinical factors. Radiomic information was evaluated based on several constant sequences, including enhanced T1-weighted sequences (with arterial, portal, and delayed phases), T2 FSE sequences, and dual-echo sequences. The performance of InceptionV4 was cross-validated in the training cohort (n = 127) and internally validated in an independent cohort (n = 64), with comparisons against single important clinical factors and radiologists in terms of receiver operating characteristic (ROC) curves. Class activation mapping was used to visualize the InceptionV4 model. The InceptionV4 model achieved an AUC of 0.871 (95% confidence interval [CI] 0.761-0.981) in the cross-validation cohort and an AUC of 0.826 (95% CI 0.682-0.970) in the internal validation cohort; these two models performed better than did the other methods (AUC ranges 0.783-0.873 and 0.708-0.806 for cross- and internal validations, respectively; P < 0.01). The present InceptionV4 model, which integrates radiomic information and clinical factors, helps predict the treatment response of unresectable HCC patients receiving HAIC treatment.

Modified Conjoint Fascial Sheath and Levator Muscle Complex Suspension for the Correction of Simple Severe Congenital Ptosis in Pediatrics and the Effect on Refractive Status.

PURPOSE: To evaluate the outcomes of modified combined fascia sheath and levator muscle complex suspension to correct severe congenital ptosis in pediatrics and the effect on refractive status. METHODS: This prospective, case series study enrolled patients (aged ≤18 years) with simple severe congenital ptosis at Zhongshan Ophthalmic Center. All patients were treated with combined fascia sheath + levator muscle suspension and followed up for 3 months. Preoperative and postoperative cycloplegic refraction and the best-corrected visual acuity were performed. The types of astigmatism include with-the-rule, against-the-rule, and oblique. RESULTS: Thirty-six patients (50 eyes) were enrolled. The mean age was 7.11 ± 3.72 years. The surgery success rate was 90.0%. Following surgery, the eyelid contour of all eyes exhibited natural symmetry and satisfactory curvature. The eyelid height difference in OUs was ≤1 mm for 42 eyes. For 47 eyes, the eyelid crease was symmetry. Two eyes had conjunctival prolapse, and 1 eye developed trichiasis. After surgery, cylinder power changed from mean -1.14 ± 1.27 D to -1.54 ± 1.25 D (p < 0.001) and best-corrected visual acuity improved from mean 0.205 ± 0.217 logarithm of the minimum angle of resolution to 0.168 ± 0.176 logarithm of the minimum angle of resolution (p = 0.048). The quantities of with-the-rule increased from 35 eyes to 41 eyes, oblique from 4 eyes to 6 eyes, while against-the-rule decreased from 11 eyes to 3 eyes (p = 0.01). CONCLUSIONS: Combined fascia sheath + levator muscle suspension under general anesthesia is effective and safe for severe congenital ptosis in pediatrics. However, astigmatism increased and the types of astigmatism changed after surgery.

Corneal Morphological and Biomechanical Changes in Thyroid-Associated Ophthalmopathy.

PURPOSE: This study aimed to evaluate corneal morphological and biomechanical changes in patients with thyroid-associated ophthalmopathy (TAO) and their correlations with activity and severity. METHODS: Patients diagnosed with TAO were recruited and divided into groups by activity and severity. All subjects underwent a complete ophthalmic examination, including magnetic resonance imaging. Corneal topography was measured using a Pentacam device, and biomechanical parameters were obtained using a CorVis ST tonometer. Correlations among the corneal parameters, clinical activity score, and NOSPECS score were analyzed. Areas under the receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of corneal changes for active and severe TAO. RESULTS: Fifty-three eyes with TAO and 16 healthy eyes were enrolled in our study. The back elevation, CorVis biomechanical index, tomographic and biomechanical index, stiffness parameter at the first applanation, deviation from normality in back elevation, relational thickness, and overall deviation from normality were significantly increased in patients with TAO (all P <0.05), whereas the smallest corneal thickness, maximum Ambrósio relational thickness, and deformation amplitude (DA) ratio were significantly decreased (all P <0.05). The clinical activity score was strongly positively correlated with back elevation (γ = 0.515, P <0.001). The NOSPECS score was strongly positively correlated with relational thickness and tomographic and biomechanical index (γ = 0.429 and 0.515, P <0.001) and negatively correlated with maximum Ambrósio relational thickness (γ = -0.53, P <0.001). Moreover, maximum Ambrósio relational thickness and the Ambrósio relational thickness through the horizontal meridian showed desirable diagnostic capacity in distinguishing mild TAO from moderate-severe TAO (areas under the receiver operating characteristic curve, 0.799 and 0.769). CONCLUSIONS: Corneal morphological and biomechanical changes were found in patients with TAO, which might be related to the presence of inflammation. Measurements of corneal morphological and biomechanical parameters could serve as references in evaluating TAO.

A synergistic regulation works in matrix stiffness-driven invadopodia formation in HCC.

Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin ß1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin ß1/RhoA/ROCK1/MLC2 and Piezo1/Ca2+/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.

Surgical Outcomes of Standardized Endoscopical Deep Medial Orbital Decompression in Dysthyroid Optic Neuropathy.

INTRODUCTION: The aim of the study was to standardize the endoscopic deep medial orbital decompression surgery for better relief of optic nerve compression in dysthyroid optic neuropathy (DON). METHODS: A total of 128 eyes from patients received the standardized endoscopic deep medial orbital decompression surgery were recruited in this study. The efficacy of the procedure was assessed at a 1-month follow-up by the best-corrected visual acuity (VA), visual field (VF), and visual evoked potential (VEP). Clinical data were collected to explore the factors that affected visual recovery. Oxygen saturation of retinal blood vessels, retinal thickness, and vessel density were measured to demonstrate the potential recovery mechanisms. RESULTS: After surgery, the ratio of extraocular muscle volume in the orbital apex to orbital apex volume significantly decreased from 44.32 ± 22.31% to 36.82 ± 12.02% (p < 0.001). 96.87% of eyes' final VA improved; average VA improved from 0.93 ± 0.73 to 0.50 ± 0.60 at 1 week (p < 0.001) and 0.40 ± 0.53 at 1 month (p < 0.001). Postoperatively, VF and VEP also improved, the oxygen saturation of retinal arteries increased, and the retinal thickness was reduced. Preoperative VA, visual impairment duration, and clinical activity score evaluation were associated with visual recovery. CONCLUSION: In this study, we standardized the endoscopic deep medial orbital decompression, of which key point was to relieve pressure in the orbital apex and achieved satisfactory visual recovery in DON patients.

Quality of Vision in Eyes with Chronic Dacryocystitis After Endoscopic Dacryocystorhinostomy.

Purpose: To assess the quality of vision (QOV) of patients with chronic dacryocystitis and explore the impact of endoscopic dacryocystorhinostomy (En-DCR) on patients' QOV, with the aim of increasing clinicians' attention to the potential QOV changes in patients with chronic dacryocystitis. Patients and Methods: Chronic dacryocystitis patients who attended the Department of Oculoplastics, Zhongshan Ophthalmic Center, Sun Yat-sen University from January 2022 to June 2022 and had En-DCR were included. The QOV was evaluated preoperatively and postoperatively using the Quick-contrast sensitivity function test (qCSF) and the OPD ScanIII comprehensive visual quality analyser, and the contrast sensitivity function (CSF), higher-order aberrations (HOAs), and modulation transfer function (MTF) data were recorded. Results: Thirty-eight patients with chronic dacryocystitis were included. QOV analysis of those with monocular chronic dacryocystitis revealed that HOAs were significantly higher in affected eyes than in contralateral eyes (P < 0.05), and CSF and MTF were significantly lower in affected eyes than in contralateral eyes (P < 0.05). One month after En-DCR, patients' HOAs, CSF, and MTF were significantly improved (P < 0.05), and there was no statistically significant difference in the effect of intraoperative combined silicone intubation versus no intubation on QOV (P > 0.05). Conclusion: Chronic dacryocystitis can significantly affect the QOV of patients. Successful En-DCR significantly improves the CSF, HOAs and MTF, which can effectively improve the QOV.

Predicting risk of postpartum hemorrhage associated with vaginal delivery of twins: A retrospective study.

Many studies have only focused on the risk factors for postpartum hemorrhage (PPH) in singleton vaginal deliveries and twin cesarean deliveries. We analyzed the factors of influencing PPH occurrence in twin vaginal deliveries and developed a nomogram for clinical application. This retrospective study included 274 pregnant women with twin pregnancies who were hospitalized for delivery from January 2014 to December 2018. The patients opted for vaginal delivery and experienced spontaneous labor. Univariate analysis of PPH risk factors was performed. Multivariate analysis was performed using the least absolute shrinkage and selection operator (LASSO) to obtain relevant factors and build a prediction model, which was presented as a nomogram. The model was internally validated by bootstrap self-sampling method. Model accuracy was evaluated with the concordance index (C-index). There were 36 (13.14%) and 238 (86.9%) patients in the PPH and no PPH groups, respectively. Univariate analysis identified twin chorionicity, hypertensive disorders complicating pregnancy (HDCP), anemia in pregnancy, delivery mode of the second twin, oxytocin use during labor, postpartum curettage, cervical laceration, intrapartum fever, fibrinogen degradation products (FDP), and platelet count (PLT) as significant PPH factors. On multivariate analysis, HDCP, anemia in pregnancy, intrapartum fever, oxytocin use during labor, fetal distress, PLT, direct bilirubin, and FDP were noted as significant PPH factors and were included in the prediction model. A C-index of 0.816 was noted after internal validation, and the calibration curve showed good consistency. We developed a model to predict PPH risk in the vaginal delivery of twin pregnancies and visualized it with a nomogram that can be applied clinically to assess PPH risk and aid PPH prevention.

NLRP3/IL-1ß induced myeloid-derived suppressor cells recruitment and PD-L1 upregulation promotes oxaliplatin resistance of hepatocellular carcinoma.

Oxaliplatin is commonly used as the first-line chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). Unfortunately, the acquired resistance, limits the effectiveness of oxaliplatin and the underlying mechanisms remain unknown. Therefore, we explored the role of NOD-like receptor protein 3 (NLRP3)/IL-1ß in mediating oxaliplatin resistance in HCC. We observed that NLRP3/IL-1ß expression was much higher in oxaliplatin-resistant HCC cells. To further understand its impact on drug resistance, we knocked down NLRP3 and observed that it sensitized HCC cells to the growth-inhibitory effects of oxaliplatin and induced cell apoptosis. NLRP3/IL-1ß overexpressing tumor cells also attracted polymorphonuclear myeloid-derived suppressor cells. Using mouse models, we demonstrated that NLRP3/IL-1ß inhibition by short hairpin RNA or MCC950 effectively overcame oxaliplatin resistance. Furthermore, NLRP3/IL-1ß inhibition resulted in reduced expression of PD-L1. We also found that PD-L1 antibody combined with NLRP3/IL-1ß blockade displayed significant antitumor effect in HCC. Overall, our study provides compelling evidence supporting the essential role of NLRP3/IL-1ß in conferring resistance to oxaliplatin and reshaping the immunosuppressive microenvironment in HCC. Targeting NLRP3/IL-1ß presents a potential therapeutic target for overcoming oxaliplatin resistance and reshaping microenvironment of HCC.

Development of a Combined Oxidative Stress and Endoplasmic Reticulum Stress-Related Prognostic Signature for Hepatocellular Carcinoma.

BACKGROUND: Oxidative stress and endoplasmic reticulum stress are important components of the cellular stress process, which plays a critical role in tumor initiation and progression. METHODS: First, the correlation between oxidative stress and endoplasmic reticulum stress was detected in 68 human hepatocellular carcinoma (HCC) tissue microarray samples by immunohistochemistry. Differentially expressed oxidative stress- and endoplasmic reticulum stressrelated genes (OESGs) then were screened in HCC. Next, an OESGs prognostic signature was constructed for HCC in the training cohort (TCGA-LIHC from The Cancer Genome Atlas), by least absolute shrinkage and selection operator Cox and stepwise Cox regression analyses, and was verified in the external cohort (GSE14520 from the Gene Expression Omnibus). The MCP counter was employed to evaluate immune cell infiltration. The C-index was used to evaluate the predictive power of prognostic signature. Finally, a prognostic nomogram model was constructed to predict the survival probability of patients with HCC based on the results of Cox regression analysis. RESULTS: We demonstrated a positive correlation between oxidative stress and ER stress in human HCC samples. We then identified five OESGs as a prognostic signature consisting of IL18RAP, ECT2, PPARGC1A, STC2, and NQO1 for HCC. Related risk scores correlated with tumor stage, grade, and response to transcatheter arterial chemoembolization therapy, and the higher risk score group had less T cells, CD8+ T cells, cytotoxic lymphocytes and natural killer cell infiltration. The C-index of our OESGs prognostic signature was superior to four previously published signatures. Furthermore, we developed a nomogram based on the OESGs prognostic signature and clinical parameters for patients with HCC that is an effective quantitative analysis tool to predict patient survival. CONCLUSION: The OESGs signature showed excellent performance in predicting survival and therapeutic responses for patients with HCC.

HbA1c: an independent risk factor for dysthyroid optic neuropathy.

Background: We aimed to explore the frequencies of islet ß-cell autoantibodies and insulin resistance (IR) in thyroid-associated ophthalmopathy (TAO) and identify specific diabetes mellitus (DM) indicators as early predictors for dysthyroid optic neuropathy (DON). Methods: Ninety-eight TAO patients (57 DON and 41 non-DON patients) and 48 healthy control (HC) participants were recruited for this prospective cross-sectional study. Serum thyroxine, serum thyroid autoantibodies, serum humoral immune markers against islet ß-cell, fasting plasma glucose (FPG), fasting serum insulin (FINS), fasting c-peptide (FCP), and glycosylated hemoglobin A1 (HbA1c) were measured. Logistic regression analysis was used to evaluate the correlation of patients' age, body mass index (BMI), FPG, HbA1c, and related indexes of islet ß-cell function to the occurrence of DON. Results: The DON group had higher FPG (P<0.001, 0.016) and HbA1c (P<0.0001, P<0.001) levels than the HC and non-DON groups. The homeostasis model assessment (HOMA)-IR level was the highest in the DON group (HC 2.15 ± 0.89, non-DON 2.41 ± 1.24, and DON 2.82 ± 2.65), while the HOMA-ß level was the lowest (HC 101.8 ± 44.75%, non-DON 102.9 ± 54.61%, and DON 88.29 ± 52.75%), with no significant differences (P=1, P>0.05). On univariate analysis, age (P=0.006), BMI (P=0.022), history of steroid use (P=0.014), FPG (P=0.013), and HbA1c (P=0.001) levels were significantly associated with the presence/absence of DON. In addition, after adjusting for potential confounds, the HbA1c level was an independent factor associated with DON (P=0.009, OR=4.012). Conclusions: HbA1c is an independent risk factor for DON. Given the interconnected link between thyroid dysfunction and DM, the use of HbA1c as a potential biomarker for DON warrants further investigation.

Mechanical stress induced EndoMT in endothelial cells through PPARγ downregulation.

Portal hypertension is a group of clinical syndromes induced by increased portal system pressure due to various etiologies including cirrhosis. When portal hypertension develops, the portal vein dilates and endothelial cells (ECs) in the portal vein are subjected to mechanical stretch. In this study, elastic silicone chambers were used to simulate the effects of mechanical stretch on ECs under portal hypertension. We found that mechanical stretch decreased PPARγ expression in ECs by blocking the PI3K/AKT/CREB signaling pathway or increasing NEDD4-mediated ubiquitination and degradation of PPARγ. Moreover, PPARγ downregulation triggered Endothelial-to-mesenchymal transition (EndoMT) in ECs under stretch by promoting Smad3 phosphorylation. The PPARγ agonist rosiglitazone mitigated stretch-induced EndoMT in vitro and alleviated EndoMT of the portal vein endothelium in cirrhotic rats.

Microbial distributions in the conjunctiva and lacrimal sacs of patients with chronic dacryocystitis in a tertiary hospital.

BACKGROUND: The aim was to clarify the distributions of bacteria in the conjunctival sac and lacrimal sac in patients with chronic dacryocystitis. METHODS: In total, 297 (322 eyes) chronic dacryocystitis patients who underwent nasal endoscopic dacryocystorhinostomy (EN-DCR) were included. Conjunctival sac secretions from the affected eye were collected preoperatively, and lacrimal sac retention fluid from the affected side in the same patient was collected intraoperatively. Bacterial culture and drug sensitivity testing were performed to determine bacterial distributions. RESULTS: In total, 127 bacterial isolates (49 species) were detected in 123 eyes in the conjunctival group, with a positivity rate of 38.2% (123/322); 85 bacterial isolates (30 species) were detected in 85 eyes in the lacrimal sac group, with a positivity rate of 26.4% (85/322). The positivity rates were significantly different (P = 0.001) between two groups. The gram-negative bacilli proportion in the lacrimal sac group (36/85, 42.4%) was significantly higher than that in the conjunctival sac group (37/127, 29.2%) ( P = 0.047). Positive conjunctival sac secretion culture (123/322) was significantly associated with increased ocular secretion (281/322, 87.3%) (P = 0.002). Among the culture-positive bacteria in the conjunctival sac group and the lacrimal sac group, 30/127, 23.6% and 43/127, 26.7% and 21/85, 24.7% and 20/85, 23.5% were resistant to levofloxacin and tobramycin, respectively. CONCLUSIONS: This study illustrated differences in bacterial distributions between conjunctival sac secretions and retained lacrimal sac fluid in chronic dacryocystitis patients, with a higher proportion of gram-negative bacilli in lacrimal sac secretions. The ocular surface flora in chronic dacryocystitis patients is partially resistant to levofloxacin and tobramycin, which need to be considered by ophthalmologists.

Controlled Synthesis of MOF-Derived Nano-Microstructure toward Lightweight and Wideband Microwave Absorption.

Correlating metal-organic framework (MOF) synthesis processes and microwave absorption (MA) enhancement mechanisms is a pioneer project. Nevertheless, the correlation process still relies mainly on empirical doctrine, which hardly corresponds to the specific mechanism of the effect on the dielectric properties. Hereby, after the strategy of modulation of protonation engineering and solvothermal temperature in the synthesis route, the obtained sheet-like self-assembled nanoflowers were constructed. Porous structures with multiple heterointerfaces, abundant defects, and vacancies are obtained by controlled design of the synthesis procedure. The rearrangement of charges and enhanced polarization can be promoted. The designed electromagnetic properties and special nano-microstructures of functional materials have significant impact on their electromagnetic wave energy conversion effects. As a consequence, the MA performance of the samples has been enhanced toward broadband absorption (6.07 GHz), low thickness (2.0 mm), low filling (20%), and efficient loss (-25 dB), as well as being suitable for practical environmental applications. This work establishes the connection between the MOF-derived materials synthesis process and the MA enhancement mechanism, which provides insight into various microscopic microwave loss mechanisms.

Changes in the VOC of Fruits at Different Refrigeration Stages of 'Ruixue' and the Participation of Carboxylesterase MdCXE20 in the Catabolism of Volatile Esters.

Aroma is a crucial quality attribute of apple fruit, which significantly impacts its commercial value and consumer choice. Despite its importance the volatile aroma substances produced by the new variety 'Ruixue' after harvest remain unclear. In this study, we utilized headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) to investigate the changes in volatile substances, fruit hardness, crispness, and related aroma synthase activity of commercially mature 'Ruixue' apples during cold storage. Our findings revealed a gradual decline in fruit firmness and brittleness of 'Ruixue' apples during cold storage, with hexyl acetate, hexyl caproate, and hexyl thiocyanate being the main hexyl esters detected. To gain a better understanding of the metabolic pathway of esters, we identified 42 MdCXE gene members that are associated with ester degradation. Through RT-qPCR analysis, we discovered that carboxylesterase MdCXE20 exhibited higher expression levels compared to other MdCXE genes during cold storage. To confirm the role of MdCXE20, we conducted a transient injection of apple fruits and observed that overexpression of MdCXE20 led to the degradation of esters such as hexyl hexanoate, butyl hexanoate, butyl 2-methylbutyrate, hexyl butyrate, and hexyl 2-methylbutyrate. The results of the study showed that the virus-induced gene silencing of MdCXE20 found the opposite results. Additionally, the esters of OE-MdCXE20 callus showed a lower content of ester VOC than the control callus, according to the homologous stable transformation of 'Wanglin' callus. Overall, these findings suggest that the MdCXE20 gene plays a crucial role in the decrease of esters in 'Ruixue' apples, which ultimately affects their flavor.

Critical role of transcriptome-wide m6A methylation in the aqueous humor of patients with pseudoexfoliation glaucoma.

N6-methyladenosine (m6A) modification is one of the most common types of methylation modifications in eukaryotic mRNA. However, its role in the pathogenesis of pseudoexfoliation glaucoma (PXG) has not yet been reported. To enhance understanding in this regard, we assessed the m6A methylome in the aqueous humor of patients with PXG. MeRIP-Seq and RNA-Seq analyses were performed to compare the m6A methylomes and gene expression profiles of the aqueous humor of patients with PXG with those of patients with age-related cataract (ARC). Colorimetric m6A quantification was performed to detect global m6A levels. Quantitative reverse transcription PCR confirmed the expression of m6A-related enzymes and mRNAs in both groups. Results showed significantly higher aqueous humor m6A levels in the PXG group than in the ARC group. Five m6A-related enzymes, including METTL3, YTHDC2, HNRNPA2B1, HNRNPC, and LRPPRC, were significantly up-regulated in PXG specimens. We also observed 9728 m6A-modified peaks related to 6126 gene transcripts in the PXG group, with more than 250 genes containing one m6A peak (hypomethylated or hypermethylated). The distribution of the m6A peaks was enriched in coding sequences and 3'-untranslated regions for both groups. GGAC motif structures were also significantly enriched. Bioinformatics analysis further revealed that m6A plays a critical role in extracellular matrix formation and histone deacetylation. Additionally, MMP14, ADAMTSL1, FN1, and HDAC1 showed significant changes in m6A methylation and mRNA expression in the PXG group. Therefore, m6A methylation may regulate extracellular matrix composition in PXG and METTL3 may be a pivotal regulator of this process. In the future, it would be necessary to investigate MMP14, ADAMTSL1, FN1, and HDAC1, which are potential target genes.