GSK3ß and UCHL3 govern RIPK4 homeostasis via deubiquitination to enhance tumor metastasis in ovarian cancer.

Receptor-interacting protein kinase 4 (RIPK4) is increasingly recognized as a pivotal player in ovarian cancer, promoting tumorigenesis and disease progression. Despite its significance, the posttranslational modifications dictating RIPK4 stability in ovarian cancer remain largely uncharted. In this study, we first established that RIPK4 levels are markedly higher in metastatic than in primary ovarian cancer tissues through single-cell sequencing. Subsequently, we identified UCHL3 as a key deubiquitinase that regulates RIPK4. We elucidate the mechanism that UCHL3 interacts with and deubiquitinates RIPK4 at the K469 site, removing the K48-linked ubiquitin chain and thus enhancing RIPK4 stabilization. Intriguingly, inhibition of UCHL3 activity using TCID leads to increased RIPK4 ubiquitination and degradation. Furthermore, we discovered that GSK3ß-mediated phosphorylation of RIPK4 at Ser420 enhances its interaction with UCHL3, facilitating further deubiquitination and stabilization. Functionally, RIPK4 was found to drive the proliferation and metastasis of ovarian cancer in a UCHL3-dependent manner both in vitro and in vivo. Importantly, positive correlations between RIPK4 and UCHL3 protein expression levels were observed, with both serving as indicators of poor prognosis in ovarian cancer patients. Overall, this study uncovers a novel pathway wherein GSK3ß-induced phosphorylation of RIPK4 strengthens its interaction with UCHL3, leading to increased deubiquitination and stabilization of RIPK4, thereby promoting ovarian cancer metastasis. These findings offer new insights into the molecular underpinnings of ovarian cancer and highlight potential therapeutic targets for enhancing antitumor efficacy.

CONet: Crowd and occlusion-aware network for occluded human pose estimation.

Human pose estimation has numerous applications in motion recognition, virtual reality, human-computer interaction, and other related fields. However, multi-person pose estimation in crowded and occluded scenes is challenging. One major issue about the current top-down human pose estimation approaches is that they are limited to predicting the pose of a single person, even when the bounding box contains multiple individuals. To address this problem, we propose a novel Crowd and Occlusion-aware Network (CONet) using a divide-and-conquer strategy. Our approach includes a Crowd and Occlusion-aware Head (COHead) which estimates the pose of both the occluder and the occluded person using two separate branches. We also use the attention mechanism to guide the branches for differentiated learning, aiming to improve feature representation. Additionally, we propose a novel interference point loss to enhance the model's anti-interference ability. Our CONet is simple yet effective, and it outperforms the state-of-the-art model by +1.6 AP, achieving 71.6 AP on CrowdPose. Our proposed model has achieved state-of-the-art results on the CrowdPose dataset, demonstrating its effectiveness in improving the accuracy of human pose estimation in crowded and occluded scenes. This achievement highlights the potential of our model in many real-world applications where accurate human pose estimation is crucial, such as surveillance, sports analysis, and human-computer interaction.

The efficacy and safety of 0.01% atropine alone or combined with orthokeratology for children with myopia: A meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of 0.01% atropine alone and in combination with orthokeratology for myopia control using a meta-analysis. METHODS: PubMed, Cochrane Library, and EMBASE were searched. We included eligible randomized controlled trials (RCTs), non-RCTs, and retrospective cohort studies, published up to August 1, 2022. We calculated the weighted mean difference (WMD) and 95% confidence interval (CI) for all outcomes and plotted them in forest plots. RESULTS: Fourteen studies were included; 4 and 11 in the 0.01% atropine monotherapy and atropine-orthokeratology (AOK) groups, respectively. Compared with orthokeratology (OK) alone, 0.01% atropine alone had similar effects on slowing the axial elongation (WMD: -0.00 mm; 95% CI: -0.05-0.04, p<0.31), while AOK significantly lowered axial growth. Moreover, the baseline myopic degree and duration of treatment were influential for the change in axial elongation (WMD: -0.12 mm; 95% CI: -0.17--0.07, p = 0.00001 and WMD: -0.11 mm; 95% CI: -0.15--0.108, p<0.00001, respectively). Additionally, the AOK may reduce the change rate of the spherical equivalent refraction and the accommodation amplitude (WMD: -0.13 D; 95% CI: 0.07-0.19, p<0.001 and WMD: -1.08 mm; 95% CI: -1.73--0.43, p<0.0001, respectively), and cause a slight increase in the diameter of the pupil (WMD: 0.56 mm; 95% CI: 0.43-0.70, p = 0.007). No significant differences in the uncorrected distant visual acuity, best corrected visual acuity, intraocular pressure, tear film break-up time, lipid layer thickness, and corneal endothelial cell density were found between the OK and AOK groups. CONCLUSION: In slowing the axial elongation, 0.01% atropine alone and OK alone have similar effects, while AOK is more effective than OK alone in slowing down the axial elongation. Furthermore, the baseline degree of myopia and treatment duration may affect changes in axial elongation.

Posterior corneal elevation changes during 12 month of overnight orthokeratology.

Aims: the aim of this study to investigate the elevation changes in posterior corneal surface after 12 months of orthokeratology (ortho-k) treatment. Methods: In this retrospective chart review, medical records of 37 Chinese children who wore ortho-k lenses over 12 months were reviewed. The data of only right eye were analyzed. Variables including the flat and steep keratometry of anterior and posterior corneal principal meridians, central corneal thickness (CCT), posterior thinnest elevation of cornea (PTE), posterior central elevation of cornea (PCE) and posterior mean elevation of cornea (PME) were measured by Pentacam. Variables including anterior chamber depth (ACD), lens thickness (CLT) and ocular axis length (AL) were measured by optical biometry. All variables differences between baseline and 12 months after ortho-k treatment were assessed by statistical analyses. Results: The average age of all subjects was 10.70 ± 1.75 years (range 8-15 years old). The baseline spherical equivalent (SE) was -3.26 ± 1.52 D (-0.50D to -5.00D). Both flat and steep keratometry of anterior corneal surface and CCT were significantly decreased after 12 month follow up during ortho-k treatment (both P < 0.000). Both flat and steep keratometry of posterior corneal surface were not significantly different after 12 month follow up compared with that of baseline (P = 0.426, 0.134 respectively). PCE, PTE and PME were not significantly changed over 12 months of ortho-k treatment (P = 0.051, 0.952 and 0.197 respectively). The ACD was significantly decreased in 12 month follow up during ortho-k treatment (P = 0.001). The CLT and the AL were significantly increased during this period (both P < 0.000). Conclusion: Although the anterior corneal surface was significantly changed by ortho-k lens, the posterior corneal surface did not show any changes during 12 months follow up. Simultaneously, The ACD, CLT and AL were significantly changed during this period.

Identifying a lactic acid metabolism-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.

Lactic acid, once considered as an endpoint or a waste metabolite of glycolysis, has emerged as a major regulator of cancer development, maintenance, and progression. However, studies about lactic acid metabolism-related genes (LRGs) in lung adenocarcinoma (LUAD) remain unclear. Two distinct molecular subtypes were identified on basis of 24 LRGs and found the significant enrichment of subtype A in metabolism-related pathways and had better overall survival (OS). Subsequently, a prognostic signature based on 5 OS-related LRGs was generated using Lasso Cox hazards regression analysis in TCGA dataset and was validated in two external cohorts. Then, a highly accurate nomogram was cosntructed to improve the clinical application of the LRG_score. By further analyzing the LRG_score, higher immune score and lower stromal score were found in the low LRG_score group, which presented a better prognosis. Patients with low LRG_score also exhibited lower somatic mutation rate, tumor mutation burden (TMB), and cancer stem cell (CSC) index. Three more independent cohorts (GSE126044: anti-PD-1, GSE135222: anti-PD-1, and IMvigor210: anti-PD-L1) were analyzed, and the results showed that patients in the low LRG_score category were more responsive to anti-PD-1/PD-L1 medication and had longer survival times. It was also determined that gefitinib, etoposide, erlotinib, and gemcitabine were more sensitive to the low LRG_score group. Finally, we validated the stability and reliability of LRG_score in cell lines, clinical tissue samples and HPA databases. Overall, the LRG_score may improve prognostic information and provide directions for current research on drug treatment strategies for LUAD patients.

Exploring the Potential of Exosome-Related LncRNA Pairs as Predictors for Immune Microenvironment, Survival Outcome, and Microbiotain Landscape in Esophageal Squamous Cell Carcinoma.

Accumulating studies have demonstrated the indispensable roles of exosomes and long non-coding RNAs (lncRNAs) in cancer progression and the tumor microenvironment (TME). However, the clinical relevance of exosome-related lncRNAs (ER-lncRNAs) in esophageal squamous cell carcinoma (ESCC) remains unclear. Three subtypes were identified by consensus clustering of 3459 valid ER-lncRNA pairs, of which subtype A is preferentially related to favorable prognosis, lower stromal and immune scores, and higher tumor purity scores. Higher immune cell infiltration, higher mRNA levels of immune checkpoints, higher stromal and immune scores, and lower tumor purity were found in subtype C, which presented a poor prognosis. We developed a prognostic risk score model based on 8 ER-lncRNA pairs in the GEO cohort using univariate Cox regression analysis and LASSO Cox regression analysis. Patients were divided into a high risk-score group and low risk-score group by the cut-off values of the 1-year ROC curves in the training set (GEO cohort) and the validation set (TCGA cohort). Receiver operating characteristic (ROC) curves, Decision curve analysis (DCA), clinical correlation analysis, and univariate and multivariate Cox regression all confirmed that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor in different cohorts. By further analyzing the TME based on the risk model, higher immune cell infiltration and more active TME were found in the high-risk group, which presented a poor prognosis. Patients with high risk scores also exhibited higher mRNA levels of immune checkpoints and lower IC50 values, indicating that these patients may be more prone to profit from chemotherapy and immunotherapy. The top five most abundant microbial phyla in ESCC was also identified. The best ER-lncRNAs (AC082651.3, AP000487.1, PLA2G4E-AS1, C8orf49 and AL356056.2) were identified based on machine learning algorithms. Subsequently, the expression levels of the above ER-lncRNAs were analyzed by combining the GTEx and TCGA databases. In addition, qRT-PCR analysis based on clinical samples from our hospital showed a high degree of consistency. This study fills the gap of ER-lncRNA model in predicting the prognosis of patients with ESCC and the risk score-based risk stratification could facilitate the determination of therapeutic option to improve prognoses.

Crystalline lens thickness change is associated with axial length elongation and myopia progression in orthokeratology.

AIMS: Considering individual variability in regards to the effects of orthokeratology (ortho-k) on myopia progression and controversies regarding the precise underlying mechanism, the aim of this study was to investigate several ocular measurements associated with axial length (AL) growth in children wearing ortho-k lenses. METHODS: In this retrospective chart review, medical records of 53 Chinese children who wore ortho-k lenses over the course of 12 months were reviewed. Baseline variables included age at initiation of ortho-k wear, refractive error (spherical equivalent, SE), central corneal thickness (CCT), and flat and steep keratometry of corneal principal meridians. The change of anterior chamber depth (ACD) and the change of crystalline lens thickness (CLT) between baseline and the 12-month follow-up were also analyzed. The contributions of all analyzed variables to AL change were assessed using univariate and multivariate regression analyses. RESULTS: Initially, the results of paired t-test showed that CLT and AL were significantly increased after 12 months of ortho-k wear compared with that at baseline (P = 0.001 and < 0.001). The ACD did not change significantly after 12 months compared with that at baseline (P = 0.491). Subsequently, univariate analyses showed that a reduced rate of AL elongation was found in children who were older age at initiation of ortho-k wear (P = 0.028), had greater SE (higher degree of myopia) at baseline (p = 0.006), had thicker CCT at baseline (P = 0.04), and had greater increase of CLT (P = 0.001) in 12 months. At last, only greater SE (higher degree of myopia) and greater increase of CLT were associated with smaller increases of AL in multivariable analyses, (P = 0.003 and 0.001). CONCLUSIONS: Both CLT and AL were significantly increased in children with overnight ortho-k wear after 12 months of follow-up. Greater baseline SE and greater increase of CLT were associated with less increase in AL during ortho-k wear in children with myopia.

Randomized Efficacy Trial of Conventional, TCM Herb, and TEAS on Bone Marrow Suppression in Patients with Small Cell Lung Cancer after Initial Chemotherapy.

OBJECTIVE: To compare the efficiency of transcutaneous electrical acupoint stimulation (TEAS) with those of conventional and TCM herb on bone marrow suppression in small cell lung cancer (SCLC) patients after initial chemotherapy. METHODS: We recruited 139 participants with pathologically confirmed SCLC who had not received chemotherapy. The conventional group (n = 37) received gemcitabine and cisplatin chemotherapy and routine care. The TCM herb group (n = 35) received 3 Diyushengbai tablets thrice a day for one day prior to chemotherapy and maintained during the trial. The TEAS group (n = 42) received TEAS at a frequency of 65-100 Hz with a pulse width of 100-200 µsec. Acupoints were selected from Dazhui (DU14), Geshu (BL17), Zusanli (ST36), Sanyinjiao (SP6), and Hegu (LI4) and were treated on days 1, 2, 3, 5, 8, 14, 21, and 28 of chemotherapy for 30 min each day. All three groups underwent a 28-day treatment for a total of one treatment course. Changes in the white blood cell, neutrophil, platelet, and hemoglobin indices on day 1 before chemotherapy and days 5, 8, 11, 14, 21, and 28 days after chemotherapy were compared among the groups. Comfort levels of patients on day 1 before chemotherapy and days 5, 11, and 21 after chemotherapy were observed. RESULTS: Compared with the conventional group, the white blood cell counts in the TEAS group on days 8 (7.07 ± 2.11 vs. 5.97 ± 2.10 × 109/L) and 14 (6.14 ± 1.51 vs. 5.07 ± 2.41 × 109/L) of chemotherapy and that in the TCM herb group on day 14 (6.63 ± 3.44 vs. 5.07 ± 2.41 × 109/L) of chemotherapy were increased (P < 0.05). Compared with the conventional group, the neutrophil count in the TEAS group on days 5 (4.28 ± 1.54 vs. 3.01 ± 1.41 × 109/L), 8 (3.75 ± 1.21 vs. 2.77 ± 1.17 × 109/L), 11 (3.46 ± 1.31 vs. 2.31 ± 1.24 × 109/L), 14 (3.18 ± 1.29 vs. 2.07 ± 1.14 × 109/L), and 21 (4.67 ± 1.31 vs. 3.58 ± 1.23 × 109/L) of chemotherapy and that in the TCM herb group on day 5 (3.88 ± 1.05 vs. 3.01 ± 1.41 × 109/L) of chemotherapy were increased (P < 0.05). Compared with the conventional group, the platelet count of patients in the TEAS group increased on days 5 (264.7 ± 64.1 vs. 201.0 ± 55.7 × 109/L), 8 (251.3 ± 74.9 vs. 188.2 ± 65.8 × 109/L), 11 (236.7 ± 74.9 vs. 181.3 ± 84.3 × 109/L), and 14 (238.3 ± 75.9 vs. 192.8 ± 95.8 × 109/L) of chemotherapy (P < 0.05). Compared with the TCM herb group, the platelet count in the TEAS group increased on days 5 (264.7 ± 64.1 vs. 216.3 ± 57.9 × 109/L), 8 (251.3 ± 74.9 vs. 213.7 ± 70.3 × 109/L), 11 (236.7 ± 74.9 vs. 181.3 ± 84.3 × 109/L), and 21 (254.8 ± 81.8 vs. 213.9 ± 82.6 × 109/L) of chemotherapy (P < 0.05). Compared with the conventional group, the hemoglobin level in the TCM herb group increased on day 14 (135.03 ± 28.06 vs. 122.09 ± 12.63 g/L) of chemotherapy (P < 0.05). Compared with the conventional group, the comfort score of the TEAS group increased on days 5 (78.31 ± 10.21 vs. 70.18 ± 9.34 score) and 11 (80.07 ± 10.44 vs. 72.11 ± 9.47 score) of chemotherapy (P < 0.05). CONCLUSION: TEAS is an effective and safe treatment modality for improving bone marrow suppression in SCLC patients after initial chemotherapy. TEAS improved comfort levels more effectively than did conventional and TCM herb.

Effect of Transcutaneous Electrical Acupoint Stimulation on One-Lung Ventilation-Induced Lung Injury in Patients Undergoing Esophageal Cancer Operation.

OBJECTIVE: To investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on one-lung ventilation-induced injury in patients undergoing esophageal cancer operation. METHODS: The participants (n = 121) were randomly assigned into TEAS and sham groups. The TEAS group was given transcutaneous electrical stimulation therapy. The acupoints selected were Feishu (BL13), Hegu (L14), and Zusanli (ST36) and were treated 30 minutes before induction of anesthesia; treatment lasts 30 minutes. The sham group was connected to the electrode on the same acupoints, but electronic stimulation was not applied. The levels of oxygenation index (PaO2/FiO2) and alveolar-arterial oxygen tension difference (A-aDO2) before one-lung ventilation (T1), 30 minutes after one-lung ventilation (T2), 2 hours after one-lung ventilation (T3), and 1 hour after the operation (T4) and the levels of serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) at T1, T2, T3, and 24 hours after the operation (T5) were taken as the primary endpoints. The incidence of postoperative pulmonary complications, removal time of thoracic drainage tube, and length of hospital stay were taken as the secondary endpoints. RESULTS: Compared with that, in the sham group, the level of PaO2/FiO2 in the TEAS group was significantly increased at T2, T3, and T4, and the level of A-aDO2 was significantly reduced at T2 and T3 (P < 0.05). Besides, compared with that, in the sham group, the level of serum TNF-α at T2, T3, and T5, as well as the level of serum IL-6 at T3 and T5, was significantly reduced, whereas the level of serum IL-10 at T3 was significantly increased (P < 0.05). The incidences of pulmonary infection and pleural effusion in the TEAS group were significantly lower than that in the sham group, and the removal time of thoracic drainage tube and the length of hospital stay in the TEAS group were significantly shorter than that in the sham group (P < 0.05). CONCLUSIONS: TEAS could effectively increase the levels of PaO2/FiO2 and IL-10, reduce the levels of A-aDO2, TNF-α, and IL-6, and reduce the incidence of pulmonary complications. Moreover, it could also contribute to shorten the removal time of thoracic drainage tube and the length of hospital stay.

[The relationship between the effect of amlodipine on carotid intimal-medial thickness and angiotensin converting enzyme genotypes in elderly hypertensive patients].

OBJECTIVE: To investigate the association between the anti-atherosclerotic effects of amlodipine and angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in elderly essential hypertensive (EH) patients. METHODS: A total of 220 EH patients were treated with amlodipine (2.5 - 10 mg, once daily) for twelve months and complete data were obtained from 208 patients with genotypes of II (n = 90), ID (n = 91) and DD (n = 27). The indices of carotid arterial were compared before and post amlodipine treatment in patients with identical genotype and among different ACE genotypes and each genotype post therapy. RESULTS: The carotid mean intimal-medial thickness (MIMT) was slightly decreased in EH patients with ID and DD genotypes and significantly decreased in EH patients with II genotype (0.96 +/- 0.12 vs. 0.92 +/- 0.13, P < 0.01) compared to pre-treatment values. The decreased degree of MIMT (DeltaMIMT) in II genotype was significantly higher in II genotype than those in ID or DD genotype (0.05 +/- 0.03 vs. 0.01 +/- 0.02, 0.01 +/- 0.03 respectively, P < 0.01). The post treatment plaque score (PS) in patients with II genotype was significantly reduced (4.85 +/- 2.51 vs. 3.90 +/- 2.36, P < 0.05). Multivariate linear regression analysis showed the baseline SBP, the decreased degree of SBP (DeltaSBP) and the II genotype were the major factors affecting the DeltaMIMT. CONCLUSION: Hypertensive patients carrying II genotype ACE genotype are the best responders for the anti-atherosclerotic effects of amlodipine.

Assessment of coronary artery disease with second harmonic myocardial perfusion contrast echocardiography.

OBJECTIVE: To assess the relationship between myocardial regional perfusion using second harmonic myocardial contrast echocardiography (MCE) by venous injection of Levovist and coronary artery stenosis detected by coronary angiography to determine whe ther MCE can be used to detect coronary artery disease (CAD) and its sensitivity and specificity for detecting CAD. METHODS: Thirty-six patients who underwent coronary artery angiography and MCE formed the study groups. Ten myocardial segments (5 each in the apical two- and four-chamber views) from the images were scored for detecting myocardial perfusion as follows: 1, normal perfusion; 2, decreased perfusion; and 3, perfusion defect. The arteries were classified as normal or diseased. The diseased arteries were classified into three groups according to the perfusion scores. RESULTS: There were significant differences in coronary diameter stenosis among the different perfusion score groups (P < 0.001). There were 10 total occluded arteries, and the myocardial perfusion scores were different because of different collateral circulation. In the normal perfusion group (Group A), the coronary diameter stenosis was 65% +/- 12%, and the myocardial perfusion score index was 1 +/- 0.00. In the decreased perfusion group (Group B), the average coronary diameter stenosis was 82% +/- 8%, and the myocardial perfusion score was 1.93 +/- 0.16. The diameter stenosis was less than 85% in 63% of the coronary arteries (including diameter stenosis < or = 75% in 12% of the vessels). The diameter stenosis was 85%-90% in 22% of the coronary arteries and > 90% in 15% of the arteries. In the perfusion defect group (Group C), the average diameter stenosis was 90% +/- 6%, and the myocardial perfusion score index was 2.89 +/- 0.24. The diameter stenosis was > or = 85% in 94% of the coronary arteries, and the diameter stenosis was < 85% and > 75% only in 6% of the coronary arteries. The overall sensitivity and specificity of MCE in identifying angiographic coronary diameter stenosis was 67% and 100%, respectively. The false negative rate was 32.6% for the 108 coronary arteries. Further subdivided analysis showed the sensitivities in Groups A, B and C were 0, 100%, and 100%, respectively. The sensitivity increased with increased lumen diameter stenosis of coronary arteries. CONCLUSIONS: There is a close relationship between coronary artery stenosis and MCE perfusion scores. MCE with venous injection of new generation contrast can define the presence of CAD and lesion graded classifications. Some disagreements between perfusion score and coronary diameter of stenosis may indicate other factors such as different collateral circulation, which should be further investigated. As artery stenosis increases, the sensitivity of MCE is increased.