Mechanistic regulation of FOXO transcription factors in the nucleus.

FOXO proteins represent evolutionarily conserved transcription factors (TFs) that play critical roles in responding to various physiological signals or pathological stimuli, either through transcription-dependent or -independent mechanisms. Dysfunction of these proteins have been implicated in numerous diseases, including cancer. Although the regulation of FOXO TFs shuttling between the cytoplasm and the nucleus has been extensively studied and reviewed, there's still a lack of a comprehensive review focusing on the intricate interactions between FOXO, DNA, and cofactors in the regulation of gene expression. In this review, we aim to summarize recent advances and provide a detailed understanding of the mechanism underlying FOXO proteins binding to target DNA. Additionally, we will discuss the challenges associated with pharmacological approaches in modulating FOXO function, and explore the dynamic association between TF, DNA, and RNA on chromatin. This review will contribute to a better understanding of mechanistic regulations of eukaryotic TFs within the nucleus.

Study of Iron Complex Photosensitizer with Hollow Double-Shell Nano Structure Used to Enhance Ferroptosis and Photodynamic Therapy.

Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2 ) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2 -HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+ , which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2 O2 and enhances the production of singlet oxygen (1 O2 ) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2 -HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.

Prognostic value of geriatric nutritional risk index and prognostic nutritional index in hepatocellular carcinoma.

BACKGROUND: The geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) are considered prognostic factors for several cancers. This study aimed to investigate the relationship between the GNRI and PNI for survival outcomes in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 1666 patients with HCC who underwent hepatectomy. Restricted cubic spline regression was used to analyze the relationship between the GNRI and PNI for recurrence and mortality. Cox proportional hazards regression analysis was used to evaluate the risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Interaction analysis was performed to investigate the comprehensive effects of the GNRI, PNI, and subgroup parameters on the prognosis of patients with HCC. RESULTS: The risks of death and recurrence decreased rapidly and gradually stabilized as the GNRI and PNI scores increased. Patients with lower GNRI and PNI scores had significantly shorter OS and RFS rates than those with higher scores. Multivariate analysis showed that high GNRI [HR and 95%CI = 0.77 (0.70-0.85), P < 0.001] and PNI [HR and 95%CI = 0.77 (0.70-0.86), P < 0.001] scores were associated with decreased mortality risk. This trend was maintained by confounding variables in adjusted models despite partial interactions with clinical factors. The combined GNRI and PNI analysis showed that HCC patients with high GNRI and PNI had longer OS and RFS. CONCLUSIONS: The GNRI and PNI showed good survival predictions in patients with HCC. Combining the GNRI with PNI may help predict the prognosis of patients (age>18 years) with HCC after hepatectomy.

[Effects of circ-SFMBT2 on Proliferation, Migration and Invasion of Acute Myeloid Leukemia Cells by Regulating miR-491-5p/HOXA9 Axis].

OBJECTIVE: To explore the effects and molecular mechanism of circ-SFMBT2 on the proliferation, migration and invasion of acute myeloid leukemia (AML) cells. METHODS: Bone marrow samples from 35 pediatric AML patients and 35 healthy controls in Henan Provincial Children's Hospital from April 2015 to April 2017 and human bone marrow stromal cell lines (HS-5) and AML cell lines (HL-60, THP-1, U-937 and Kasumi-1) were collected. The expressions of circ-SFMBT2, miR-491-5p and homeobox A9 (HOXA9) in bone marrow samples and cells were detected by RT-qPCR and Western blot. The Pearson method was used to analyze the correlation of circ-SFMBT2, miR-491-5p and HOXA9 mRNA expression levels in bone marrow samples of AML patients. HL-60 cells were cultured in vitro and divided into 5 groups: Control, si-NC, si-circ-SFMBT2, si-circ-SFMBT2+anti-NC and si-circ-SFMBT2+anti-miR-491-5p, HL-60 cells were transfected with si-NC, si-circ-SFMBT2, anti-NC, and miR-491-5p inhibitor with Lipofectamine™ 3000. RT-qPCR and Western blot were performed to detect the expression levels of circ-SFMBT2, miR-491-5p and HOXA9 in cells of each group. The proliferation activity of HL-60 cells in each group was detected by CCK-8 assay at 24, 48 and 72 h after transfection, respectively. The apoptosis rate was detected by flow cytometry. The migration and invasion abilities of cells were detected by Transwell assay. The regulatory roles of circ-SFMBT2, miR-491-5p and HOXA9 in AML cells were verified by dual-luciferase reporter gene assay, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) experiments. RESULTS: The expression levels of circ-SFMBT2 and HOXA9 mRNA were increased in bone marrow samples and cell lines (HL-60, THP-1, U-937 and Kasumi-1) of children with AML (P <0.001), while the expression level of miR-491-5p was significantly decreased (P <0.001). Pearson correlation analysis showed that the expression levels of circ-SFMBT2 and miR-491-5p in bone marrow samples of AML children were negatively correlated (r =-0.905), miR-491-5p was also negatively correlated with HOXA9 mRNA (r =-0.930), while the expression levels of HOXA9 mRNA and circ-SFMBT2 was positively correlated (r =0.911). The overall survival rate of AML children with high expression of circ-SFMBT2 was significantly decreased than those with low expression of circ-SFMBT2 (P <0.05). Silencing of circ-SFMBT2 could greatly up-regulate the expression of miR-491-5p, decrease the expression of HOXA9, inhibit the proliferation, migration and invasion of AML cells, and promote cell apoptosis (P <0.05). Down-regulation of miR-491-5p expression greatly attenuated the inhibitory effects of circ-SFMBT2 silencing on cell proliferation, migration and invasion (P <0.05). Dual-luciferase reporter gene assay, RNA pull-down and RIP experiments confirmed that circ-SFMBT2 could target miR-491-5p and negatively regulate the expression of miR-491-5p in AML, and HOXA9 was the target of miR-491-5p. CONCLUSION: Silencing of circ-SFMBT2 may inhibit the proliferation, migration and invasion of AML cells by regulating the miR-491-5p/HOXA9 axis.

Treatment of persistent flap closure with fluid gas exchange after inverted internal limiting membrane flap technique for idiopathic macular hole.

We evaluated the results of fluid-gas exchange (FGE) for long-term flap closure of idiopathic macular holes (MH) using the inverted internal limiting (ILM) flap technique. We retrospectively included eyes showing flap closure without complete MH closure and connection of separate macular tissue 1 month postoperatively after the inverted ILM flap technique was detected by ocular coherence tomography at follow-up. Eyes remained flap closure at 2 months after surgery further underwent in-office FGE with 16% C3F8. Of the 153 eyes using the inverted ILM flap technique for idiopathic MH between June 2015 and November 2018, 10 eyes (6.99%) remained flap closure at 1 month postoperatively. Among 10 eyes, 5 eyes (50%) showed flap closure at 2 months postoperatively further underwent FGE for complete MH closure, while the remaining 5 eyes (50%) progressed directly to normal macular structures at 2 months postoperatively. Improvement in vision of all flap closure from baseline was significant (P = .015), with a mean baseline vision of 1.19 [Snellen equivalent (SE), 20/307] ±â€…0.52 logMAR and the mean final vision of 0.63 (SE, 20/85) ±â€…0.38 logMAR. The group that underwent FGE showed better final vision of 0.45 (SE, 20/75) ±â€…0.23 logMAR than the group that did not undergo FGE (0.81 [SE, 20/128] ±â€…0.44 logMAR). All eyes achieved complete MH closure, including the eyes that underwent FGE in a mean period of 5.60 months (range 3-10 months) after the inverted ILM flap technique. Eyes that underwent FGE achieved a higher rate of foveal restoration [complete external limiting membrane 80%; complete ellipsoid zone (EZ) 60%] than those that did not receive FGE (complete external limiting membrane: 40%; complete EZ: 10%). Eyes with persistent flap closure for more than 2 months postoperatively that underwent FGE showed accelerated complete MH closure, better final vision, and foveal restoration.

Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up.

BACKGROUND: Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. METHODS: We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case-control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. RESULTS: Through a case-control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032-2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. CONCLUSION: The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

Positive effects of dietary Clostridium butyricum supplementation on growth performance, antioxidant capacity, immunity and viability against hypoxic stress in largemouth bass.

The effects of dietary supplementation of Clostridium butyricum (CB) on growth performance, serum biochemistry, antioxidant activity, mRNA levels of immune-related genes and resistance to hypoxia stress were studied in largemouth bass. Feed with CB0 (control, 0 CFU/kg), CB1 (4.3×108 CFU/kg), CB2 (7.5×108 CFU/kg), CB3 (1.5×109 CFU/kg) and CB4 (3.2×109 CFU/kg) CB for 56 days, and then a 3 h hypoxic stress experiment was performed. The results showed that dietary CB significantly increased the WGR (weight gain rate), SGR (specific growth rate), PDR (protein deposition rate) and ISI (Intestosomatic index) of largemouth bass (P<0.05). Hepatic GH (growth hormone)/IGF-1 (insulin-like growth factor-1) gene expression was significantly upregulated in the CB3 and CB4 groups compared with the CB0 group (P<0.05), while the FC (feed conversion) was significantly decreased (P<0.05). Serum TP (total protein) and GLU (glucose) levels were significantly higher in the CB4 group than in the CB0 group (P<0.05), while the contents of serum AST (aspartate transaminase), ALT (alanine transaminase), AKP (alkline phosphatase) and UN (urea nitrogen) in CB4 were significantly lower than those in CB0 (P<0.05). T-AOC (total antioxidant capacity), SOD (superoxide dismutase), CAT (catalase), POD (peroxidase) and GSH-Px (glutathione peroxidase) activities were significantly higher in CB3 and CB4 groups than in CB0 group (P<0. 05). The liver MDA (malondialdehyde) content of CB1, CB2, CB3 and CB4 groups was significantly higher than that of CB0 group (P<0. 05). The relative expressions of IL-1ß (interleukin 1ß), TNF-α (tumor necrosis factor α) and TLR22 (toll-like receptor-22) genes in CB2, CB3 and CB4 groups were significantly lower than those in CB0 group (P<0.05). The relative expression of IL-8 (malondialdehyde) and MyD88 (Myeloid differentiation factor 88) genes in the CB4 group was significantly lower than that in the CB0 group (P<0.05). The liver LZM (lysozyme) content of CB2, CB3 and CB4 groups was significantly higher than that of CB0 group (P<0. 05). The relative expression of IL-10 (interleukin 10) and TGF-ß (transforming growth factor ß) genes in the CB4 group was significantly higher than that in the CB0 group (P<0.05). Under hypoxic stress for 3 h, the CMR of CB0 group was significantly higher than that of CB1, CB2, CB3 and CB4 groups (P<0.05). Dietary CB can improve the growth performance and resistance to hypoxic stress of largemouth bass by regulating the expression of GH/IGF-1 gene and inflammatory factors and inhibiting TLR22/MyD88 signaling pathway.

Robot-assisted laparoscopic enucleation in the treatment of leiomyosarcoma of urinary bladder: A case report. / æœºå™¨äººè¾ åŠ©è ¹è ”é•œä¸‹å‰œé™¤æœ¯æ²»ç–—è†€èƒ±å¹³æ»‘è‚Œè‚‰ç˜¤1例.

Leiomyosarcoma of urinary bladder (LMS-UB) is a highly malignant mesenchymal tumor, accounting for less than 0.5% of all bladder malignancies, with a predominant clinical presentation of hematuria. Here we report a case of low-grade LMS-UB. A 44-year-old male patient was admitted to the hospital with urodynia for 2 weeks. The patient's pelvis CT showed a mass on the right part of the bladder. For this reason, he was initially diagnosed with bladder cancer. We performed a robot-assisted laparoscopic enucleation of the bladder tumor and low-grade LMS-UB was diagnosed with the histopathological examination. He underwent 5 cycles of adjuvant chemotherapy after surgery. At 19months postoperative follow-up, the patient had no symptoms, recurrence, or distant metastasis. There is no report on the treatment of LMS-UB with minimally invasive enucleation worldwide. This case provides a new comprehensive treatment method of enucleation combined with adjuvant chemotherapy for early low-grade LMS-UB to reduce complications and improve patients' quality of life after surgery.

Hmox1 is Identified as a Ferroptosis Hub Gene and Associated with the M1 Type Microglia/Macrophage Polarization in Spinal Cord Injury: Bioinformatics and Experimental Validation.

Ferroptosis and immune cell infiltration are important pathological events in spinal cord injury (SCI), but links between ferroptosis and immune microenvironment after SCI were rare reported. In our study, 77 FRDEGs were screened at 7 days after SCI. GO analysis of FRDEGs showed that aging (GO:0007568; P-value = 1.11E-05) was the most remarkable enriched for biological process, protein binding (GO:0005515; adjusted P-value = 4.44E-06) was the most significantly enriched for molecular function, cytosol (GO:0005829; adjusted P-value = 1.51E-04) was the most prominent enriched for cellular component. Meanwhile, Ferroptosis was significantly enriched both in KEGG (rno04216; adjusted P-value = 0.001) and GSEA (NES = 1.35; adjusted P-value = 0.004) analysis. Next, Hmox1 (Log2Fold change = 6.52; adjusted P-value = 0.004) was identified as one of hub genes in SCI-induced ferroptosis. In the results of immune cell infiltration analysis, proportion of microglia/macrophage was significantly increased after SCI, and Hmox1 was found to positively correlate to the M1 type microglia/macrophage abundance. Finally, effects of Hmox1 on ferroptosis and M1 type polarization were validated in vivo and in vitro. Summarily, we found that Hmox1 was the hub gene in SCI-induced ferroptosis and associated with the M1 type polarization.

Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities.

Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide  additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.

The emerging nanomedicine-based technology for non-small cell lung cancer immunotherapy: how far are we from an effective treatment.

Non-small cell lung cancer (NSCLC) is a prominent etiology of cancer-related mortality. The heterogeneous nature of this disease impedes its accurate diagnosis and efficacious treatment. Consequently, constant advancements in research are imperative in order to comprehend its intricate nature. In addition to currently available therapies, the utilization of nanotechnology presents an opportunity to enhance the clinical outcomes of NSCLC patients. Notably, the burgeoning knowledge of the interaction between the immune system and cancer itself paves the way for developing novel, emerging immunotherapies for treating NSCLC in the early stages of the disease. It is believed that with the novel engineering avenues of nanomedicine, there is a possibility to overcome the inherent limitations derived from conventional and emerging treatments, such as off-site drug cytotoxicity, drug resistance, and administration methods. Combining nanotechnology with the convergence points of current therapies could open up new avenues for meeting the unmet needs of NSCLC treatment.

PUS1 May Be a Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma.

Objective: The mechanisms of pseudouridine synthase (PUS) are not definite in hepatocellular carcinoma (HCC), the objective of this study is to investigate the effect of PUS genes in HCC. Materials and Methods: Differentially expressed and prognostic gene of PUS enzymes was identified based on The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. For the identified gene, pseudouridine synthase 1 (PUS1), was used for further research. The clinicopathological feature of PUS1 was analyzed by Student's t-test. Prognostic significance was explored by Kaplan-Meier (KM) analysis and Cox proportional hazards regression model. Receiver operating characteristic (ROC) curve was applied to appraise diagnostic and prognostic value. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Gene Set Enrichment Analysis (GSEA) were implemented to explore mechanism of PUS1. A Guangxi cohort was applied to verify differential expression. In vitro cell experiments were implemented to investigate the influence for proliferation, reactive oxygen species (ROS) level, migration, and invasion of HCC cells after a knockdown of PUS1. Results: PUS1 was significantly overexpressed in HCC tissues, and patients with high PUS1 were related to unpromising clinicopathological features. Survival analysis revealed high PUS1 expression was associated with a poor overall survival (OS) and 1 year-recurrence free survival (RFS), was an independent risk factor. Meanwhile, ROC curve showed that PUS1 had a diagnostic and prognostic significance to HCC. Functional enrichment analysis implied that PUS1 may be involved in metabolic pathways, mitochondrial function, non-alcoholic fatty liver disease (NAFLD), and some important carcinogenic pathways. Cell assays revealed that knockdown of PUS1 significantly constrained the migration, proliferation, invasion and improved the ROS level of HCC cells. Conclusion: PUS1 may be a prognostic biomarker and a underlying treatment target for HCC.

Regulatory mechanism of DHRS2-modified human umbilical cord mesenchymal stem cells-derived exosomes in prostate cancer cell proliferation and apoptosis.

Prostate cancer (PCa) is a prevalent cause of morbidity and mortality. DHRS2-modified human umbilical cord mesenchymal stem cells-derived exosomes (hUC-MSCs-derived exos) function in PCa. We explored the mechanism of DHRS2-modified hUC-MSCs-derived exos in PCa cell malignant behaviors. DHRS2 expression levels in WPMY-1 cells and 4 PCa cell lines were detected by RT-qPCR and Western blot. 22Rv1/DU145 cells with high/low DHRS2 expression were selected to establish the low/high DHRS2 expression models by transfection. Cell proliferation and apoptosis were detected by CCK-8, colony formation assays, and flow cytometry. hUC-MSCs were identified by oil red O, alizarin staining, and flow cytometry. Exos were extracted from hUC-MSCs by ultracentrifugation and identified by transmission electron microscopy, Nano series-Nano-ZS, and Western blot. DU145 cells were selected for in vitro study to further study the effects of DHRS2-modified exos on cell proliferation and apoptosis. The effect of DHRS2-modified exos on cell cycle distribution was detected by flow cytometry. DHRS2 was repressed in PCa cells. DHRS2 overexpression suppressed PCa cell proliferation and promoted apoptosis. Exos were successfully isolated from hUC-MSC. DHRS2-modified hUC-MSCs-derived exos carried DHRS2 into PCa cells and blocked malignant behaviors. Briefly, DHRS2 was repressed in PCa cells. DHRS2-modified hUC-MSCs-derived exos blocked PCa cell proliferation and enhanced apoptosis.

Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: A real-world study.

Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer.

Clinical Significance of Visual Training in Improving Visual Function After Retinal Detachment in Adolescents.

Context: Epidemiological data has shown that retinal detachment (RD) can occur at any age but has a poor prognosis in the adolescent population, which can cause huge obstacles to their life and learning. Although medications can achieve some curative effect, they have potential side effects and differences in individual efficacy. Objective: • The study intended to explore the clinical significance of visual training in improving recovery of postoperative visual function after external reduction of retinal detachment in adolescent patients. Design: The research team designed a prospective randomized controlled study. Setting: The study took place at Guiyang First People's Hospital in Guiyang, Guizhou, China. Participants: Participants were 110 adolescents with retinal detachments who underwent external reduction surgery, each on one eye for 110 eyes in total, and who were patients at the hospital between June 2015 and June 2019. Intervention: The research team assigned 52 participants to the visual-function training group, the intervention group, and 58 participants to the control group, according to the random-number-table method. Each group participated in training method for six months. Outcome Measures: To compare the groups, the research team measured visual function using the Visual Function scale (VF), binocular fusion function using the Worth Four Light Test (W4LT), and stereoscopic vision using the Titmus Stereo Test. The team obtained preoperative and postoperative data-at baseline, one day before surgery and postoperatively at one month and 3 months, and postintervention at 6 months. Results: Both groups had visual impairment after surgery. For visual function, the intervention group's scores after surgery increased gradually and were significantly higher than those of the control group at each follow-up time (P < .05). No significant difference in binocular fusion function existed between the groups at baseline or at one month after surgery (P > .05). At 3 months after surgery and postintervention, the proportions of participants in the intervention group with normal binocular fusion function were 86.54% and 88.46%, respectively, compared to that of the control group, at 68.97% and 70.69%, respectively. The intervention group's recovery was significantly better than that of the control group at 3 months after surgery and postintervention, at P < .028 and P < .022, respectively. No significant difference existed between the groups in stereoscopic vision at baseline, at 9.62% and 12.07%, respectively (P > .05). The proportion of participants in the intervention group with normal, binocular, stereoscopic vision increased gradually, and at one and 3 months after surgery and postintervention was 67.31%, 82.69%, and 88.46%, respectively. The intervention group's recovery was significantly better than that of the control group at one and 3 months after surgery and postintervention, at P < .028, P < .010, and P < .013, respectively. Conclusions: Visual training can effectively promote the recovery of visual function after external reduction of RD in adolescents and improve patients' prognoses. Moreover, long-term persistence can achieve significant effects, making the training worthy of clinical promotion.

Case report: hepatic arterial infusion chemotherapy combined with sintilimab and lenvatinib for conversion therapy of colorectal cancer liver metastases.

Background: Liver metastasis is one of the most common causes of death in patients with colorectal cancer. Therefore, improving the treatment effect of liver metastatic carcinoma of colorectal cancer is also one of the effective ways to improve the survival time of patients with colorectal cancer. The main treatment method for liver metastasis of colorectal cancer is preoperative neoadjuvant chemotherapy through intravenous administration. However, no one has reported a conversion therapy approach for the treatment of colorectal cancer liver metastases patients through arterial infusion chemotherapy combined with targeted agents and PD-1 monoclonal antibody. This case reports a conversion therapy method of liver metastases of colorectal cancer by hepatic arterial infusion chemotherapy (HAIC), sintilimab injection combined with lenvatinib to achieve radical resection of liver metastatic carcinoma after treatment. Case presentation: The patient was a 69-year-old man who had previously undergone laparoscopic left hemicolectomy for descending colorectal cancer and multiple interventional and surgical treatments for hepatocellular carcinoma. During this treatment, the patient underwent radiological and serological tests, and primary liver cancer was considered at the initial diagnosis stage. Therefore, this liver malignant tumor lesion was treated according to the primary liver cancer treatment protocol before surgical resection. Therefore, the patient received HAIC combined with sintilimab injection and lenvatinib. After three treatment cycles, radiological examination showed no obvious tumor activity, alpha-fetoprotein (AFP) decreased to normal, protein induced by vitamin K absence or antagonist II (PIVKA II) decreased significantly, and the curative effect was evaluated as complete remission. Subsequently, we performed surgical resection of this liver lesion. The pathological response of left lobe tumor was partial remission (PR). Most of the tumors were necrotic and the necrosis rate was greater than 95%. A small amount of live tumor tissue remains (<5%). The pathological classification of this tumor was confirmed as moderately differentiated adenocarcinoma by immunohistochemical staining of multiple tumor indicators in the pathology department. No significant adverse drug events were observed in this patient during treatment. Conclusion: Hepatic arterial infusion chemotherapy combined with sintilimab injection and lenvatinib conversion therapy provides the opportunity for radical surgical resection of colorectal cancer liver metastases.

The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α.

Prolyl hydroxylase domain protein 2 (PHD2)-catalyzed modification of hypoxia-inducible factor (HIF)-α is a key event in oxygen sensing. We previously showed that the zinc finger of PHD2 binds to a Pro-Xaa-Leu-Glu (PXLE) motif. Here, we show that the zinc finger binds to this motif in the ribosomal chaperone nascent polypeptide complex-α (NACA). This recruits PHD2 to the translation machinery to cotranslationally modify HIF-α. Importantly, this cotranslational modification is enhanced by a translational pause sequence in HIF-α. Mice with a knock-in Naca gene mutation that abolishes the PXLE motif display erythrocytosis, a reflection of HIF pathway dysregulation. In addition, human erythrocytosis-associated mutations in the zinc finger of PHD2 ablate interaction with NACA. Tibetans, who have adapted to the hypoxia of high altitude, harbor a PHD2 variant that we previously showed displays a defect in zinc finger binding to p23, a PXLE-containing HSP90 cochaperone. We show here that Tibetan PHD2 maintains interaction with NACA, thereby showing differential interactions with PXLE-containing proteins and providing an explanation for why Tibetans are not predisposed to erythrocytosis.

Experimental and Numerical Evaluation on the Performance of Perfobond Leiste Shear Connectors in Steel-SFRCC Composite Beams.

The difference between the shear performances of Perfobond Leiste (PBL) shear connectors embedded in steel fiber-reinforced cementitious composite (SFRCC) structure and normal strength concrete (NC) structure was investigated by push-out tests and finite element (FE) simulations. Push-out tests were carried out on nine steel-SFRCC specimens and nine steel-NC specimens. The mechanical behavior of the PBL shear connector was examined according to the failure modes, load-slip curves, and strain distribution laws of the push-out specimens. Experimental results revealed that the extension of cracks in SFRCC was hindered by steel fibers, and the number and width of cracks in SFRCC were smaller than those in NC. The failure mode of the steel-SFRCC specimens and the single-hole steel-NC specimens was the shear failure of the penetrating reinforcement, whereas that of the multi-hole NC specimens was concrete slab cracking. The ultimate shear bearing capacity of PBL shear connectors in the steel-SFRCC specimens was 47.8% greater than that in the steel-NC specimens. Furthermore, an FE model verified by the test results was established to conduct parametric analyses. It was found that the hole diameter and thickness of the steel plate and the yield strength of the penetrating rebar greatly affected the shear bearing capacity of PBL shear connectors. Finally, based on the experimental and FE simulation results, an expression for calculating the ultimate shear bearing capacity of PBL shear connectors in the steel-SFRCC composite structure was developed by considering the bearing effects of concrete dowels, penetrating rebars, and end parts.

Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance.

Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify Miat as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of Miat results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. Miat expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of Miat using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to Miat in stem-like MB cells. Like the loss of Miat, the loss of Mtdh reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA Miat in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.

Experimental and Numerical Analyses of Stud Shear Connectors in Steel-SFRCC Composite Beams.

To investigate the shear performance and failure mechanism of stud shear connectors in steel fiber-reinforced cementitious composite (SFRCC) beams, six steel-SFRCC and six steel-normal strength concrete (NC) push-out specimens with two heights (80 mm, 120 mm) and three diameters (14 mm, 18 mm, 22 mm) of stud connectors were prepared. The experimental results revealed that the stud shearing failure was the main failure mode of all push-out specimens. In comparison to the steel-NC specimens, the development of cracks in the SFRCC beams was efficiently restrained due to the existence of high-strength steel fibers added to the normal concrete. The shear resistance and stiffness of studs in the steel-SFRCC beams were, respectively, 22.3% and 15.1% greater than those in the steel-NC specimens; however, their ductility was reduced, and the stud shear connectors failed in advance. The finite element (FE) model was developed and verified by push-out test results. FE analysis results indicated that the shear resistance of stud shear connectors was significantly improved with the increase in the concrete compressive strength, the stud diameter and tensile strength, whereas the aspect ratio of studs had a small impact on the ultimate resistance of stud shear connectors. Based on the as-obtained push-out experiment and FE analysis results, empirical formulas were presented to predict the load-slip curves and ultimate shear resistance of stud shear connectors in the steel-SFRCC specimens, and higher accuracy and a wider application range were obtained than with previous formulas.