Temporal landscape and translational regulation of A-to-I RNA editing in mouse retina development.

BACKGROUND: The significance of A-to-I RNA editing in nervous system development is widely recognized; however, its influence on retina development remains to be thoroughly understood. RESULTS: In this study, we performed RNA sequencing and ribosome profiling experiments on developing mouse retinas to characterize the temporal landscape of A-to-I editing. Our findings revealed temporal changes in A-to-I editing, with distinct editing patterns observed across different developmental stages. Further analysis showed the interplay between A-to-I editing and alternative splicing, with A-to-I editing influencing splicing efficiency and the quantity of splicing events. A-to-I editing held the potential to enhance translation diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated effect on gene translation. CONCLUSIONS: Overall, this study presents a temporally resolved atlas of A-to-I editing, connecting its changes with the impact on alternative splicing and gene translation in retina development.

The Study of SRSF1 Regulates Abnormal Alternative Splicing of BCL2L11 and the Role in Refractory Acute Ayeloid Leukemia.

INTRODUCTION: Abnormalities in splicing factors, such as mutations or deregulated expression, can lead to aberrant splicing of target genes, potentially contributing to the pathogenesis of acute myeloid leukemia (AML). Despite this, the precise mechanism underlying the abnormal alternative splicing induced by SRSF1, a splicing factor associated with poor AML prognosis, remains elusive. METHODS: Using strict splicing criteria, we globally screened for alternative splicing(AS) events in NPMc-positive and NPMc-negative AML samples from TCGA. An AS network associated with AML prognosis was then established. Functional assays, including CCK-8, flow cytometry, and Western blot, were conducted on K562 and THP-1 cells overexpressing SRSF1. Cell viability following 72-hour Omipalisib treatment was also assessed. To explore the mechanism of SRSF1-induced AS, we created a BCL2L11 miniGene with a site-specific mutation at its branch point. The AS patterns of both wild-type and mutant miniGenes were analyzed following SRSF1 overexpression in HEK-293T, along with the subcellular localization of different spliceosomes. RESULTS: SRSF1 was significantly associated with AML prognosis. Notably, its expression was markedly upregulated in refractory AML patients compared to those with a favorable chemotherapy response. Overexpression of SRSF1 promoted THP-1 cell proliferation, suppressed apoptosis, and reduced sensitivity to Omipalisib. Mechanistically, SRSF1 recognized an aberrant branch point within the BCL2L11 intron, promoting the inclusion of a cryptic exon 3, which in turn led to apoptosis arrest. CONCLUSIONS: Overexpression of SRSF1 and the resulting abnormal splicing of BCL2L11 are associated with drug resistance and poor prognosis in AML.

Baicalin enhances the chemotherapy sensitivity of oxaliplatin-resistant gastric cancer cells by activating p53-mediated ferroptosis.

Gastric cancer is one of the most common malignant tumors, and chemotherapy is the main treatment for advanced gastric cancer. However, chemotherapy resistance leads to treatment failure and poor prognosis in patients with gastric cancer. Multidrug resistance (MDR) is a major challenge that needs to be overcome in chemotherapy. According to recent research, ferroptosis activation is crucial for tumor therapeutic strategies. In this work, we explored the solution to chemoresistance in gastric cancer by investigating the effects of the Chinese medicine monomer baicalin on ferroptosis. Baicalin with different concentrations was used to treat the parent HGC27 and drug-resistant HGC27/L cells of gastric cancer. Cell viability was measured by CCK8, and synergistic effects of baicalin combined with oxaliplatin were evaluated using Synergy Finder software. The effects of baicalin on organelles and cell morphology were investigated using projective electron microscopy. Iron concentration, MDA production and GSH inhibition rate were measured by colorimetry. ROS accumulation was detected by flow cytometry. The ferroptosis-related genes (IREB2, TfR, GPX4, FTH1), P53, and SLC7A11 were analysed by Western blot, and the expression differences of the above proteins between pretreatment and pretreatment of different concentrations of baicalin, were assayed in both parental HGC27 cells and Oxaliplatin-resistant HGC27/L cells. Mechanically, Baicalin disrupted iron homeostasis and inhibits antioxidant defense, resulting in iron accumulation, lipid peroxide aggregation, and specifically targeted and activated ferroptosis by upregulating the expression of tumor suppressor gene p53, thereby activating the SLC7A11/GPX4/ROS pathway mediated by it. Baicalin activates ferroptosis through multiple pathways and targets, thereby inhibiting the viability of oxaliplatin-resistant gastric cancer HGC27/L cells and enhancing the sensitivity to oxaliplatin chemotherapy.

Immunophenotype of myeloid granulocytes in Chinese patients with BCR::ABL1-negative myeloproliferative neoplasms.

Typical BCR::ABL1-negative myeloproliferative neoplasms (MPN) are mainly referred to as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofbrosis (PMF). Granulocytes in MPN patients are involved in their inflammation and form an important part of the pathophysiology of MPN patients. It has been shown that the immunophenotype of granulocytes in MPN patients is altered. We used flow cytometry to explore the immunophenotype of MPN patients and correlate it with clinical parameters. The results showed that PMF patients and PV patients had higher CD15+CD11b+ granulocytes than ET patients and normal controls. When grouped by gene mutation, changes in the granulocyte immunophenotype of MPN patients were independent of the JAK2V617F and CALR mutations. There was no significant heterogeneity in immunophenotype between ET patients and Pre-PMF, and between Overt-PMF and Pre-PMF patients. Granulocytes from some MPN patients showed an abnormal CD13/CD16 phenotype with a significant increase in mature granulocytes on molecular and cytomorphological grounds, and this abnormal pattern occurred significantly more frequently in PMF patients than in ET patients. CD15-CD11b- was negatively correlated with WBC and Hb and positively correlated with DIPSS score, whereas high CD10+ granulocytes were significantly and negatively associated with prognostic system IPSS and DIPSS scores in PMF patients. In conclusion, this study demonstrates the landscape of bone marrow granulocyte immunophenotypes in MPN patients. MPN patients, especially those with PMF, have a significant granulocyte developmental overmaturation phenotype. CD10+ granulocytes may be involved in the prognosis of PMF patients.

Could Cerebral Inflammatory Lesions be the Cellular Origin of Primary Central Nervous System Lymphoma?

INTRODUCTION: Primary central nervous system lymphoma (PCNSL) presents a diagnostic enigma due to the inherent absence of lymphoid tissue in the central nervous system (CNS). The hypothesis posits that lymphocytes infiltrating the CNS during inflammatory responses could represent a cellular source for PCNSL, challenging traditional understandings of its etiology. PATIENT CONCERNS: In 2 illustrative cases, patients presented with neurological symptoms initially misdiagnosed as encephalitis and demyelinating disease, respectively. These diagnoses were established based on clinical assessments and initial biopsy findings. DIAGNOSIS: Subsequent biopsies, conducted months after the first signs of disease, confirmed the diagnosis of PCNSL in both patients. Identifying CD20-positive tumor cells was pivotal, indicating a B-cell lymphoma origin. INTERVENTIONS: Treatment strategies included high-dose methotrexate chemotherapy for both patients. In addition, the second patient underwent adjuvant whole-brain radiotherapy after the chemotherapy regimen. OUTCOMES: The therapeutic approach significantly reduced tumor size in both cases, with no evidence of recurrence observed during the follow-up period. This outcome underscores the potential efficacy of the chosen interventions. CONCLUSION: In response to inflammatory lesions, lymphocyte infiltration into the CNS may serve as a pivotal origin for tumor cells in PCNSL. These cases highlight the complexity of diagnosing CNS disorders and suggest that various forms of encephalitis in the early stages could influence the prognosis of lymphoma. This insight into the cellular origins and treatment responses of PCNSL contributes to a broader understanding of its pathophysiology and management.

The role of green tea intake in thromboprophylaxis of venous thromboembolism in patients with cancer.

Background: Green tea intake has been reported to improve the clinical outcomes of patients with cardiovascular diseases or cancer. It may have a certain role in the development of venous thromboembolism (VTE) among cancer patients. The current study aimed to address this issue, which has been understudied. Methods: We carried out a retrospective study to explore the role of green tea intake in cancer patients. Patients with and without green tea intake were enrolled in a 1:1 ratio by using propensity scoring matching. The primary and secondary outcomes were VTE development and mortality 1 year after cancer diagnosis, respectively. Results: The cancer patients with green tea intake (n = 425) had less VTE development (10 [2.4%] vs. 23 [5.4%], p = 0.021), VTE-related death (7 [1.6%] vs. 18 [4.2%], p = 0.026), and fatal pulmonary embolism (PE) (3 [0.7%] vs. 12 [2.8%], p = 0.019), compared with those without green tea intake (n = 425). No intake of green tea was correlated with an increase in VTE development (multivariate hazard ratio (HR) 1.758 [1.476-2.040], p < 0.001) and VTE-related mortality (HR 1.618 [1.242-1.994], p = 0.001), compared with green tea intake. Patients with green tea intake less than 525 mL per day had increased VTE development (area under the curve (AUC) 0.888 [0.829-0.947], p < 0.001; HR1.737 [1.286-2.188], p = 0.001) and VTE-related mortality (AUC 0.887 [0.819-0.954], p < 0.001; HR 1.561 [1.232-1.890], p = 0.016) than those with green tea intake more than 525 mL per day. Green tea intake caused a decrease in platelet (p < 0.001) instead of D-dimer (p = 0.297). The all-cause mortality rates were similar between green tea (39 [9.2%]) and non-green tea (48 [11.3%]) intake groups (p = 0.308), whereas the VTE-related mortality rate in the green tea intake group (7 [1.6%]) was lower than that of the non-green tea intake group (18 [4.2%]) (p = 0.026). The incidences of adverse events were similar between the green tea and non-green tea intake groups. Conclusion: In conclusion, the current study suggests that green tea intake reduces VTE development and VTE-related mortality in cancer patients, most likely through antiplatelet mechanisms. Drinking green tea provides the efficacy of thromboprophylaxis for cancer patients.

The application of machine learning based on computed tomography images in the identification of renal tumors in children.

Background: The clinical manifestations of Wilms tumor and non-Wilms tumor in children are similar, and the only way to confirm the diagnosis is by postoperative pathology. Computed tomography (CT) is one of the main methods for preoperative diagnosis of the two, but it is also difficult to distinguish because it is easily affected by the subjective influence and the experience of the radiologists. Methods: The CT images of 82 children with renal tumors admitted to the Department of Pediatric Urology, Shandong Provincial Hospital from January 2011 to March 2022 were retrospectively analyzed. First, we drew the two-dimensional (2D) region of interest (ROI) of the largest cross-section on the corticomedullary phase (CMP) and nephrogenic phase (NP) images, and extracted seven types of 107 features in the ROI. Then, the texture features with similarity greater than 95% and repetition less than 90% were screened out, and the remaining texture features were further screened by analysis of variance (ANOVA) and recursive feature elimination (RFE). Finally, 15 texture feature were used to build the machine learning (ML) models. We used the synthetic minority oversampling technique (SMOTE) and 10-fold cross-validation to build ML models and verified them in the training, testing, and internal validation sets. The area under the receiver-operating characteristic curve (AUC) and calibration curve were used to evaluate the diagnostic performance. Results: We collected 77 CMP and 81 NP images, which were randomly divided into the training set and the testing set according to the ratio of 7:3. In the internal validation of CMP, the Mean-PCC-ANOVA-5-AE pipeline model achieved the highest AUC 0.792 [95% confidence interval (CI): 0.653-0.930], and its accuracy (ACC), sensitivity (SEN), and specificity (SPE) were 0.833, 0.539 and 0.927, respectively. Correspondingly, in NP, the Mean-PCC-ANOVA-2-LR pipeline model achieved the highest AUC 0.655 (95% CI: 0.485-0.82) in the internal validation. The ACC, SEN, and SPE were 0.696, 0.539, and 0.744, respectively. Conclusions: The ML models based on CT images have good diagnostic efficiency in differentiating Wilms tumors from non-Wilms tumors in children.

Long-term outcome of adjuvant radiotherapy upon postoperative relapse of centrally located hepatocellular carcinoma: a real-world study.

Despite that surgical resection is widely regarded as the most effective approach to the treatment of liver cancer, its safety and efficacy upon centrally located hepatocellular carcinoma (HCC) remain unsatisfactory. In consequence, seeking an integrated treatment, like combined with adjuvant radiotherapy, to enhance the prognosis of patients is of critical importance. By recruiting patients undergoing surgical resection for centrally located HCC ranging from June 2015 to 2020, they were divided into liver resection combined with adjuvant radiotherapy (LR + RT) and mere liver resection (LR) groups. The calculation of propensity score and model of Cox proportional hazards regression were utilized. 193 patients were recruited in aggregation, containing 88 ones undergoing LR + RT, while 105 handled with LR. RT was verified to be an independent factor of prognosis for relapse (HR 0.60). In propensity-score analyses, significant association existed between adjuvant radiotherapy and better disease-free survival (DFS) (Matched, HR 0.60; Adjustment of propensity score, HR 0.60; Inverse probability weighting, HR 0.63). The difference of DFS was apparent within two groups (p value = 0.022), and RT significantly down-regulated early relapse (p value < 0.05) in subgroup analysis. The calculation of E-value revealed robustness of unmeasured confounding. The combination of liver surgical resection with RT is safe and effective towards patients with centrally located HCC, which would notably enhance the prognosis and decrease the early relapse of HCC.

Widening of narrow urethral plates with lateral skin in TIP hypospadias repair: single center series.

BACKGROUND: To compare the outcomes of hypospadias repair using tubularized incised plate (TIP) urethroplasty and modified TIP with lateral skin to widen the urethral plate (WTIP). MATERIALS AND METHODS: Data were obtained from pre-pubertal boys who underwent primary hypospadias repair between May 2018 and July 2023. The cases were divided into two groups; one group underwent TIP with urethral plate ≥ 6 mm width and the other group with urethral plate width < 6 mm underwent WTIP. WTIP urethroplasty was performed by widening incisions on the outer margins of the urethral plate to incorporate penile and glandular skin lateral to the urethral plate to facilitate tubularization. Complication rates and urinary functions were compared. RESULTS: A total of 157 patients were enrolled in this study. Eighty-eight cases with narrow urethral plate were subjected to WTIP urethroplasty, and the rest were subjected to TIP urethroplasty. The preoperative glans width in WTIP group was less than that in TIP group (P < 0.001), and 44.3% had midshaft meatus in WTIP group compared to 17.4% in TIP group (P < 0.001). However, the incidences of postoperative complications (17.6% vs. 21.6%, P = 0.550) were not statistically different between the TIP and WTIP groups. In addition, both groups did not differ significantly in postoperative uroflowmetry assessment. CONCLUSIONS: The described technique helps to create an adequately caliber aesthetic neomeatus and facilitates tubularization, especially in hypospadias with a narrow urethral plate. Our data suggest that augmentation of a narrow urethral plate with WTIP has a similar surgical outcome to that of the TIP procedure in patients with a wide urethral plate.

[Gene Profile and Clinical Significance of Concomitant Mutations in CN-AML Patients with CEBPA Mutation].

OBJECTIVE: To analyze the occurrence of concomitant gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients with CEBPA mutation and its impact on the clinical characteristics and prognosis of the patients. METHODS: 151 newly diagnosed patients with CN-AML in the Second Hospital of Shanxi Medical University from June 2013 to June 2020 were analyzed retrospectively. 34 common genetic mutations associated with hematologic malignancies were detected by next-generation sequencing technology. The occurrence of concomitant gene mutations in patients with CEBPA positive and negative groups was compared, and the correlation between concomitant mutations in different functional groups and the clinical characteristics and prognosis of CN-AML patients with CEBPA mutation was analyzed. RESULTS: In 151 patients with CN-AML, 55 (36.42%) were positive for CEBPA mutation (including 36 cases of CEBPAdm and 19 cases of CEBPAsm), of which 41 (74.55%) had co-mutations with other genes. The main mutated genes were GATA2 (25.45%, 14/55), TET2 (21.82%, 12/55), FLT3 (20.00%, 11/55), NRAS (12.73%, 7/55) and WT1 (9.09%, 9/55), etc. Some cases had two or more concomitant gene mutations. Grouping the mutant genes according to their functions showed that CEBPA+ group had lower mutation rates of histone methylation (P =0.002) and chromatin modification genes (P =0.002, P =0.033), and higher mutation rates of transcription factors (P =0.037) than CEBPA- group. In 55 patients with CEBPA+ CN-AML, the platelet count at diagnosis in signaling pathway gene mutation-positive group was lower than that in the mutation-negative group (P =0.005), the proportion of bone marrow blasts in transcription factor mutation-positive group was higher than that in the mutation-negative group (P =0.003), and the onset age in DNA methylation gene mutation-positive group and chromatin modifier mutation-positive group was older than that in the mutation-negative group, respectively (P =0.002, P =0.008). DFS of CEBPA+ CN-AML patients in signaling pathway gene mutation group was shorter than that in signaling pathway gene mutation-negative group (median DFS: 12 months vs not reached) (P =0.034). Compared with DNA methylation gene mutation-negative group, CEBPA+ CN-AML patients with DNA methylation gene mutation had lower CR rate (P =0.025) significantly shorter OS and DFS (median OS: 20 months vs not reached, P =0.006; median DFS: 15 months vs not reached, P =0.049). OS in patients with histone methylation gene mutation was significantly shorter than that in the histone methylation gene mutation-negative group (median OS: 12 months vs 40 months) (P =0.008). Multivariate analysis of prognostic factors showed that the proportion of bone marrow blasts (P =0.046), concomitant DNA methylation gene mutation (P =0.006) and histone methylation gene mutation (P =0.036) were independent risk factors affecting the prognosis. CONCLUSION: CN-AML patients with CEBPA mutation have specific concomitant gene profile, and the concomitant mutations of different functional genes have a certain impact on the clinical characteristics and prognosis of the patients.

Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

BACKGROUND: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

Axial Compression Behavior of Circular Seawater and Sea Sand Concrete Columns Reinforced with Hybrid GFRP-Stainless Steel Bars.

The ductility of FRP-reinforced concrete structures is reduced by the brittleness of FRP bars. To address this issue, this study employs the hybrid reinforcement of stainless steel (SS) and GFRP bars to enhance the ductility of concrete columns. A total of 21 axially compressed seawater and sea sand concrete (SWSSC) circular columns are fabricated, including 15 hybrid GFRP and SS bar-reinforced SWSSC (GFRP-SS-SWSSC) columns, 3 GFRP bar-reinforced SWSSC (GFRP-SWSSC) columns, and 3 SS bar-reinforced SWSSC (SS-SWSSC) columns. The test results are analyzed in terms of failure mode, load-axial displacement curve, bearing capacity, and ductility. Results show that GFRP-SWSSC columns suffer brittle failure, while GFRP-SS-SWSSC columns and SS-SWSSC columns demonstrate ductile failure characteristics. Furthermore, the hybrid reinforcement contributes to an improvement in the bearing capacity of the columns. A calculation equation for the bearing capacity of axially compressed columns was established, providing reasonable predictions of bearing capacities, with a design compressive strain of 2000 µÎµ for GFRP bars. It was found that hybrid reinforcement enhanced the ductility of GFRP-SWSSC columns. In addition, when the percentage of the SS reinforcement ratio reaches 50%, the ductility indexes of the GFRP-SS-SWSSC columns closely approach those of the SS-SWSSC columns.

A Study on Interobserver and Intraobserver Reliability of the Huashan Radiologic Classification System for Cervical Spinal Cord Injury Without Fracture and Dislocation.

STUDY DESIGN: Observational study. OBJECTIVE: To assess the reproducibility and reliability of the system. BACKGROUND: The Huashan radiologic classification system for cervical spinal cord injury without fracture and dislocation (CSCIWFD) was recently proposed and found useful for clinical practice. PATIENTS AND METHODS: Patients diagnosed with CSCIWFD between 2015 and 2021 were recruited. Six spine surgeons from different institutions, three experienced and other inexperienced respectively, were trained as observers of the system, and these surgeons classified the recruited patients using the system. Then, 8 weeks later, they repeated the classification on the same patients in a different order. The interobserver and intraobserver agreement between the results was analyzed using percentage agreement, weighted kappa, and Cohen kappa (κ) statistics. RESULTS: A total of 60 patients were included in the analysis. Type I was the most frequent type (29 cases, 48.3%), followed by type II (13 cases, 21.7%), type III (12 cases, 20%), and type IV (6 cases, 10%). For all the observers, experienced observers, and inexperienced observers, the overall agreement percentages were 77.6% (κ = 0.78), 84.4% (κ = 0.84), and 72.8% (κ = 0.74), respectively, indicating substantial to nearly perfect interobserver reproducibility. A higher level of agreement was found for differentiating type I from other types, with the percentage agreement ranging from 87.8% to 94.4% (κ= 0.74-0.88). For distinguishing compression on the spinal cord (types I and II vs types III and IV) among the different groups of observers, the percentage agreement was 97.8% (κ = 0.94), indicating nearly perfect reproducibility. As for intraobserver agreement, the percentage agreement ranged from 86.7% to 96.7% (κ = 0.78-0.95), indicating at least substantial reliability. CONCLUSIONS: The Huashan radiologic classification system for CSCIWFD was easy to learn and apply in a clinical environment, showing excellent reproducibility and reliability. Therefore, it would be promising to apply and promote this system for the precise evaluation and personalized treatment strategy.

Advances in hematopoietic stem cells ex vivo expansion associated with bone marrow niche.

Hematopoietic stem cells (HSCs) are an ideal source for the treatment of many hematological diseases and malignancies, as well as diseases of other systems, because of their two important features, self-renewal and multipotential differentiation, which have the ability to rebuild the blood system and immune system of the body. However, so far, the insufficient number of available HSCs, whether from bone marrow (BM), mobilized peripheral blood or umbilical cord blood, is still the main restricting factor for the clinical application. Therefore, strategies to expand HSCs numbers and maintain HSCs functions through ex vivo culture are urgently required. In this review, we outline the basic biology characteristics of HSCs, and focus on the regulatory factors in BM niche affecting the functions of HSCs. Then, we introduce several representative strategies used for HSCs from these three sources ex vivo expansion associated with BM niche. These findings have deepened our understanding of the mechanisms by which HSCs balance self-renewal and differentiation and provided a theoretical basis for the efficient clinical HSCs expansion.

Effect of synthesis temperature on the structural morphology of a metal-organic framework and the capacitor performance of derived cobalt-nickel layered double hydroxides.

Three-dimensional interconnected nickel-cobalt layered double hydroxides (NiCo-LDHs) were prepared on nickel foam by ion exchange using a cobalt-based metal-organic framework (Co-MOF) as a template at different temperatures. The effects of the Co-MOF preparation temperature on the growth, mass, morphology, and electrochemical properties of the Co-MOF and derived NiCo-LDH samples were studied. The synthesis temperature from 30 to 50 °C gradually increased the mass of the active material and the thickness of the Co-MOF sheets grown on the nickel foam. The higher the temperature is, the larger the proportion of Co3+. ß-Cobalt hydroxide (ß-Co(OH)2) sheets were generated above 60 °C. The morphology and mass loading pattern of the derived flocculent layer clusters of NiCo-LDH were inherited from metal-organic frameworks (MOFs). The areal capacitance of NiCo-LDH shows an inverted U-shaped curve trend with increasing temperature. The electrode material synthesized at 50 °C had a tremendous specific capacitance of 7631 mF·cm-2 at a current density of 2 mA·cm-2. The asymmetric supercapacitor assembled with the sample and active carbon (AC) achieved an energy density of 55.0 Wh·kg-1 at a power density of 800.0 W·kg-1, demonstrating the great potential of the NiCo-LDH material for energy storage. This work presents a new strategy for designing and fabricating advanced green supercapacitor materials with large power and energy densities.

Effects of isorhamnetin on liver injury in heat stroke-affected rats under dry-heat environments via oxidative stress and inflammatory response.

Isorhamnetin is a natural flavonoid compound, rich in brass, alkaloids, and sterols with a high medicinal value. This study investigated the effects of isorhamnetin on liver injury and oxidative and inflammatory responses in heat-stroke-affected rats in a dry-heat environment. Fifty Sprague Dawley rats were randomly divided into five groups: normal temperature control (NC, saline), dry-heat control (DHC, saline), low-dose isorhamnetin-pretreated (L-AS, 25 mg/Kg), medium-dose isorhamnetin-pretreated (M-AS, 50 mg/Kg), and high-dose isorhamnetin-pretreated (H-AS, 100 mg/Kg) group. Saline was administered to the NC and DHC groups and corresponding concentrations of isorhamnetin were administered to the remaining three groups for 1 week. Blood and liver tissue were analyzed for oxidative stress and inflammation. The liver histopathological injury score, serum liver enzyme (alanine transaminase, aspartate transaminase, and lactate dehydrogenase), liver oxidative stress index (superoxide dismutase [SOD], catalase [CAT], and malondialdehyde), and inflammation index (tumor necrosis factor α [TNF-α], interleukin [IL]-1ß, IL-6, and lipopolysaccharides) were significantly higher in the DHC group than in the NC group (P < 0.05). These index values in the L-AS, M-AS, and H-AS groups were significantly lower than those in the DHC group (P < 0.05). The index values decreased significantly with an increase in the concentration of isorhamnetin (P < 0.05), while the index values of CAT and SOD showed the opposite tendency (P < 0.05). The expression of liver tissue nuclear factor kappa B (NF-κB), caspase-3, and heat shock protein (HSP-70) was higher in the DHC group than in the NC group (P < 0.05). Comparison between the isorhamnetin and DHC groups revealed that the expression of NF-кB and caspase-3 was decreased, while that of HSP-70 continued to increase (P < 0.05). The difference was significant for HSP-70 among all the isorhamnetin groups (P < 0.05); however, the NF-кB and caspase-3 values in the L-AS and H-AS groups did not differ. In summary, isorhamnetin has protective effects against liver injury in heat-stroke-affected rats. This protective effect may be related to its activities concerning antioxidative stress, anti-inflammatory response, inhibition of NF-кB and caspase-3 expression, and enhancement of HSP-70 expression.

Association between glyphosate exposure and osteoarthritis in US adults: Especially in people who are obese and inactive in leisure time physical activity.

OBJECTIVE: Little has been known on the effect of chronic glyphosate exposure on osteoarthritis (OA). The aim of this study was to investigate the association between glyphosate exposure and OA and to further investigate the different moderating effects of leisure time physical activity (LTPA) and body mass index (BMI) types on the association between glyphosate exposure and OA. METHODS: Cross-sectional data from 2540 participants in the 2015-2018 National Health and Nutrition Examination Survey (NHANES) were used to explore the association between glyphosate exposure and OA. Multivariate logistic regression models and restricted cubic spline models were used to investigate the association between glyphosate exposure and OA, and further analyses were conducted to determine the association between glyphosate exposure and OA under different LTPA and BMI types. RESULTS: Of the 2540 participants, 346 had OA. Participants with the highest glyphosate concentration (Q4) had a higher incidence of OA compared to participants with the lowest glyphosate concentration (Q1) (OR, 1.88; 95 % confidence interval [CI]: 1.13, 3.13), there was no nonlinear association between glyphosate and OA (non-linear P = 0.343). In the no LTPA group, glyphosate concentration in the Q4 group was correlated with OA (OR, 2.65; 95%CI: 1.27, 5.51). In the obese group, glyphosate concentration in the Q4 group was correlated with OA (OR, 2.74; 95 % CI: 1.48, 5.07). Among people with high BMI and inactive in LTPA, glyphosate concentrations in Q4 were associated with OA (OR, 2.19; 95 % CI: 1.07, 4.48). CONCLUSIONS: Glyphosate is associated with OA odd, and physical activity and moderate weight loss can mitigate this association to some degree. This study provides a scientific basis for rational prevention of OA by regulation of LTPA and BMI under glyphosate exposure.

Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy.

BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

Neuropilin-1 enhances temozolomide resistance in glioblastoma via the STAT1/p53/p21 axis.

Glioblastoma (GBM) is the most prevalent primary intracranial tumor. Temozolomide (TMZ) is the first-line chemotherapy for GBM. Nonetheless, the development of TMZ resistance has become a main cause of treatment failure in GBM patients. Evidence suggests that neuropilin-1 (NRP-1) silencing can attenuate GBM cell resistance to TMZ. This study aims to determine potential mechanisms by which NRP-1 affects TMZ resistance in GBM. The parental U251 and LN229 GBM cells were exposed to increasing concentrations of TMZ to construct TMZ-resistant GBM cells (U251/TMZ, LN229/TMZ). BALB/c nude mice were injected with U251/TMZ cells to establish the xenograft mouse model. Functional experiments were carried out to examine NRP-1 functions. Western blotting and real-time quantitative polymerase chain reaction were used to evaluate molecular protein and mRNA expression, respectively. Immunohistochemical staining showed NRP-1 and STAT1 expression in mouse tumors. The results showed that NRP-1 was highly expressed in TMZ-resistant cells. Moreover, knocking down NRP-1 attenuated the TMZ resistance of U251/TMZ cells, while upregulating NRP-1 enhanced TMZ resistance of the parental cells. NRP-1 silencing elevated GBM cell sensitivity to TMZ in tumor-bearing mice. Depleting NRP-1 reduced STAT1, p53, and p21 expression in U251/TMZ cells. STAT1 depletion offset NRP-1 silencing evoked attenuation of GBM cell resistance to TMZ. Collectively, our study reveals that NRP-1 enhances TMZ resistance in GBM possibly by regulating the STAT1/p53/p21 axis.

Enhanced outcomes in residual or recurrent craniopharyngioma: evaluating combined gamma knife and phosphorus-32 brachytherapy.

BACKGROUND: Managing residual and recurrent craniopharyngioma effectively is crucial for improving patient outcomes. This study evaluates the combined use of gamma knife and phosphorus-32 brachytherapy, offering insights into alternative, less invasive treatment strategies. METHODS: We conducted a retrospective analysis of 97 patients treated from 2010 to 2016 for residual and recurrent craniopharyngioma using gamma knife and phosphorus-32 brachytherapy. We classified these patients into three groups: superficial solid (Group A), simple cystic (Group B), and mixed cystic-solid (Group C). We assessed the treatment's effectiveness by the tumor control rates and evaluated safety by monitoring vision, endocrine function improvements, and complication rates. RESULTS: The treatment achieved complete and adequate control rates of 49.5% and 87.6%, respectively. We observed improvements in vision or visual fields in 55.1% of the patients. The morbidity rate was 15.5%. The study found no significant differences in tumor control rates among the various lesion types. CONCLUSION: The combination of gamma knife and phosphorus-32 brachytherapy presents a viable, minimally invasive alternative for treating residual and recurrent craniopharyngioma. It offers high tumor control and functional improvement rates, suggesting its potential as a preferred strategy in some instances.