RNA modifications constitute a crucial class of post-transcriptional chemical alterations that profoundly influence RNA stability and translational efficiency, thereby shaping cellular protein expression profiles. These diverse chemical marks are ubiquitously involved in key biological processes, including cell proliferation, differentiation, apoptosis, and metastatic potential, and they exert precise regulatory control over these functions. A major advance in the field is the recognition that RNA modifications do not act in isolation. Instead, they participate in complex, dynamic interactions—through synergistic enhancement, antagonism, competitive binding, and functional crosstalk—forming what is now termed the “RNA modification interactome” or “RNA modification interaction network.” The formation and functional operation of this interactome rely on a multilayered regulatory framework orchestrated by RNA-modifying enzymes—commonly referred to as “writers,” “erasers,” and “readers.” These enzymes exhibit hierarchical organization within signaling cascades, often functioning in upstream-downstream sequences and converging at critical regulatory nodes. Their integration is further mediated through shared regulatory elements or the assembly into multi-enzyme complexes. This intricate enzymatic network directly governs and shapes the interdependent relationships among various RNA modifications. This review systematically elucidates the molecular mechanisms underlying both direct and indirect interactions between RNA modifications. Building upon this foundation, we introduce novel quantitative assessment frameworks and predictive disease models designed to leverage these interaction patterns. Importantly, studies across multiple disease contexts have identified core downstream signaling axes driven by specific constellations of interacting RNA modifications. These findings not only deepen our understanding of how RNA modification crosstalk contributes to disease initiation and progression, but also highlight its translational potential. This potential is exemplified by the discovery of diagnostic biomarkers based on interaction signatures and the development of therapeutic strategies targeting pathogenic modification networks. Together, these insights provide a conceptual framework for understanding the dynamic and multidimensional regulatory roles of RNA modifications in cellular systems. In conclusion, the emerging concept of RNA modification crosstalk reveals the extraordinary complexity of post-transcriptional regulation and opens new research avenues. It offers critical insights into the central question of how RNA-modifying enzymes achieve substrate specificity—determining which nucleotides within specific RNA transcripts are selectively modified during defined developmental or pathological stages. Decoding these specificity determinants, shaped in large part by the modification interactome, is essential for fully understanding the biological and pathological significance of the epitranscriptome.

Entinostat plus exemestane in hormone receptor-positive (HR+) advanced breast cancer (ABC) previously showed encouraging outcomes. This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR + ABC that relapsed/progressed after ≥1 endocrine therapy. Patients were randomized (2:1) to oral exemestane 25 mg/day plus entinostat (n = 235) or placebo (n = 119) 5 mg/week in 28-day cycles. The primary endpoint was the independent radiographic committee (IRC)-assessed progression-free survival (PFS). The median age was 52 (range, 28-75) years and 222 (62.7%) patients were postmenopausal. CDK4/6 inhibitors and fulvestrant were previously used in 23 (6.5%) and 92 (26.0%) patients, respectively. The baseline characteristics were comparable between the entinostat and placebo groups. The median PFS was 6.32 (95% CI, 5.30-9.11) and 3.72 (95% CI, 1.91-5.49) months in the entinostat and placebo groups (HR, 0.76; 95% CI, 0.58-0.98; P = 0.046), respectively. Grade ≥3 adverse events (AEs) occurred in 154 (65.5%) patients in the entinostat group versus 23 (19.3%) in the placebo group, and the most common grade ≥3 treatment-related AEs were neutropenia [103 (43.8%)], thrombocytopenia [20 (8.5%)], and leucopenia [15 (6.4%)]. Entinostat plus exemestane significantly improved PFS compared with exemestane, with generally manageable toxicities in HR + ABC (ClinicalTrials.gov #NCT03538171).

Objective: To compare the accuracy of the centerline extracted based on CT 3D reconstruction and conventional CT 3D reconstruction in measuring the length and degree of laryngotracheal stenosis. Methods: A retrospective analysis was performed on 35 patients with laryngotracheal stenosis (including 19 cases without tracheotomy and 16 cases with tracheotomy) treated in the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Guangxi Medical University from March 2006 to March 2016, including 20 males and 15 females, whose ages ranged from 1 to 73 years, with a median age of 40.5 years. And CT data of 20 normal subjects were included in the same period, including 10 males and 10 females, whose ages ranged from 20 to 63 years, with a median age of 37.0 years. The continuous cross-sectional area of the airway perpendicular to the centerline was obtained by Mimics software. The area was compared with the discontinuous cross-sectional areas reconstructed by conventional CT 3D reconstruction software advantage workstation, also the length of cervical trachea, the length of stenosis, and the minimum airway area were compared. Multi-factor linear stepwise regression method was used to analyze the factors influencing the measuring difference between the two methods. Three patients with laryngotracheal stenosis were selected, and the measured stenosis length was compared with the surgical specimens to evaluate the accuracy of the two methods. SPSS 26.0 software was used for statistical analysis. Results: In normal people, the areas of thyroid cartilage notch, glottis, inferio thyroid cartilage margin, inferio cricoid cartilage margin, and suprasternal notch planes measured by Mimics centerline method were smaller than those measured by conventional CT 3D reconstruction (t _{thyroid cartilage notch}=4.685, t_glottis=3.791, t_{lower thyroid cartilage margin}=5.621, t_{lower cricoid cartilage margin}=6.312, t_{suprasternal notch plane}=6.436, P<0.05). And the airway length measured by Mimics centerline method from the inferior thyroid cartilage to the superior sternal notch was longer (t=9.79, P<0.001). In laryngotracheal stenosis, in the non-tracheotomy group, the minimum airway area measured by Mimics centerline method was smaller and the stenosis length was longer than those measured by the conventional CT 3D reconstruction, and the difference was statistically significant (t_{minimum airway area}=2.562, t_{stenosis length}=5.240, P<0.05). In the tracheotomy group, the stenosis length measured by Mimics centerline method was longer than that measured by conventional CT 3D reconstruction, and the difference was statistically significant (t_{stenosis length}=2.854, P<0.05). Multi-factor linear regression analysis showed that different CT thickness had a statistically significant effect on the difference in the length of stenosis measured by the two methods (b=-5.370, t=-3.306, P=0.004), and different tracheal forward angle had a statistically significant effect on the difference in the minimum airway area measured by the two methods (b=-0.419, t=-2.208, P=0.04). The difference between the measured length of the Mimics centerline method and the intraoperative specimens was less than 0.5 mm. Conclusion: The centerline extracted based on CT 3D reconstruction can precisely reflect the laryngotracheal morphology and measure laryngotracheal stenosis more accurately.
Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; China ; Constriction, Pathologic ; Female ; Humans ; Imaging, Three-Dimensional ; Infant ; Laryngostenosis/surgery* ; Male ; Middle Aged ; Retrospective Studies ; Tomography, X-Ray Computed ; Tracheal Stenosis/surgery* ; Young Adult

OBJECTIVE: To observe the effects of Casitas B lymphoma (CBL) protein on proliferation, migration and invasion of breast cancer cells and explore its mechanism of action. METHODS: Cultured breast cancer cell lines MDA-MB-231 and MCF7A were transfected with a CBL-overexpressing plasmid and a specific siRNA targeting CBL (siRNA-CBL), respectively, and the changes in cell proliferation, migration and invasion were examined using colony-forming assay, cell counting kit-8 (CCK-8), scratch test and Transwell assay. Flow cytometry and Western blotting were performed to examine the effects of CBL overexpression on cell cycle and epithelial-mesenchymal transition (EMT) of MDA-MB-231 cells, and the changes in the number of filamentous pseudopodia were observed by rhodamine- labeled phalloidin staining of the cytoskeleton. IP-mass spectrometry identified NCK2 as the interacting proteins of CBL, and their interaction was verified by immunoprecipitation and immunofluorescence co-localization experiments in HEK-293T cells transfected with the plasmids for overexpression of CBL, NCK2, or both. Cycloheximide tracking and ubiquitination assays were used for assessing the effects of CBL on stability and ubiquitination of NCK2 protein in MDA-MB-231 cells; CCK-8 and Transwell assays were used to determine the effect of NCK2 overexpression on CBL-mediated proliferation and migration of the cells. RESULTS: The proliferation, migration and invasion were significantly suppressed in MDA-MB-231 cells overexpressing CBL (P < 0.05) and significantly enhanced in MCF7 cells with CBL silencing (P < 0.01). Silencing of CBL promoted G1/S transition in MCF7 cells (P < 0.05). Overexpression of CBL significantly decreased the expressions of CDK2/4 (P < 0.01), cyclinA2/B1/D1/D3/E2 (P < 0.05), Snail, N-cadherin, claudin-1 (P < 0.05), and upregulated the expression of E-cadherin (P < 0.05). CBL silencing upregulated the expressions of CDK2/4/6 (P < 0.05), cyclin A2/B1/D1/D3/E2 (P < 0.05), Snail, vimentin, and claudin-1 (P < 0.05) and down-regulated E-cadherin expression (P < 0.05). CBL overexpression obviously reduced the number of filamentous pseudopodia in MDA-MB-231 cells, and the reverse changes were observed in MCF7 cells with CBL silencing. In MDA-MB-231 cells, CBL overexpression lowered NCK2 protein stability (P < 0.05) and promoted its ubiquitin-mediated degradation (P < 0.01). Overexpression of NCK2 obviously reversed CBL-mediated inhibition of cell proliferation and migration (P < 0.01). CONCLUSION CBL can inhibit the proliferation, migration and invasion of breast cancer cells through ubiquitination-mediated degradation of NCK2.
Humans ; Sincalide ; Lymphoma ; Cytoskeleton ; Cadherins ; MCF-7 Cells ; Oncogene Proteins ; Adaptor Proteins, Signal Transducing

Backgrounds::GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China. Methods::Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety.Results::Overall, 58 patients with FL were randomized to the G-chemo ( n = 25) and R-chemo arms ( n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09-1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%). Conclusions::The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit-risk profile in patients from China with FL.Trial registration::ClinicalTrials.gov, No. NCT01332968.

Background::To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19.Methods::This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable.Results::A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled; 66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64] vs. 42.4% [14/33]; difference of conversion rate 27.9%; 95% confidence interval [CI], 7.7%-48.1%; P = 0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 days vs. 12.0 days; hazard ratio [HR]: 1.877, 95% CI: 1.151-3.060, P = 0.006), symptom of fever (median 3.0 days vs. 12.0 days; HR: 18.990, 95% CI: 5.350-67.410, P < 0.001), as well as hospitalization (median 12.5 days vs. 20.0 days; P < 0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 days vs. 14.5 days; P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression. Conclusions::SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events.Trial registration::Chinese Clinical Trial Registry, NCT04260594, www.clinicaltrials.gov/ct2/show/NCT04260594?term= NCT04260594&draw=2&rank=1

Objective:To report a case with frontotemporal dementia (FTD) characterized by involuntary laughter.Methods:The clinical manifestations and imaging characteristics of a patient diagnosed as FTD was analyzed. Then the results of cerebrospinal fluid, positron emission tomography-computed tomography (PET-CT) and single-photon emission computed tomography examinations were collected. Blood samples were tested for related genes of FTD.Results:The patient is a 66 years old woman with insidious onset and progressing symptoms and she was mainly manifested as laughing out loud involuntarily when looking at others, childishness, stubbornness, loss of interest, irritability and other personal changes. Mild motor and language disorders were also manifested as moving slowly and speaking unclearly. The magnetic resonance imaging showed the atrophy of bilateral frontal, temporal lobe and bilateral hippocampal while the image of PET-CT showed the metabolism was reduced in different degrees. Eventually, behavioural variant of FTD was diagnosed. The result of ANXA11 gene sequencing revealed the mutation of c.107C>G(p.P36R).Conclusions:This is the first case in which a heterozygous mutation of ANXA11 gene, which is related to amyotrophic lateral sclerosis (ALS), is found in simple FTD patient, suggesting that ANXA11 gene may play an important role in the pathogenesis of FTD. This further supports the theory that ALS and FTD are spectrum disorders.

【Objective】 To investigate the effects of CSF-1 transport from dorsal root ganglion to spinal cord on activation of microglia in rats with neuropathic pain induced by vincristine. 【Methods】 A total of 54 male 10-12-week old SD rats with successful intrathecal catheterization, weighing 200-230 g, were divided into three groups according to the random number table method(n=18) : Control group(Control), Chemotherapy-induced Neuropathic Pain+intrathecal injection of IgG group(CINP), Chemotherapy-induced neuropathic pain+intrathecal injection of CSF-1 neutralizing antibody(CINP+anti). The animal model of CINP was established by intraperitoneal injection of vincristine 125 μg/kg on four alternate days. Mechanical allodynia and heat hyperalgesia were evaluated by MWT and TWL, respectively. The expression of CSF-1 and microglial marker Iba1 were detected by immunofluorescence chemistry and Western blotting. The mRNA expression of CSF-1 and Iba1 was measured by RT-PCR. The expression TNF-α, IL-6 and IL-1β were determined by ELISA. 【Results】 Compared with Control group, MWT and TWL in CINP group decreased significantly on the 3rd, 5th and 7th day after the first injection of vincristine(P<0.01), MWT and TWL in CINP+anti group increased significantly on the 5th and 7th day compared with CINP group(P<0.01). Compared with Control group, the protein and mRNA expression of CSF-1 in DRG, the mRNA expression of Iba1 in spinal cord, the protein expression of CSF-1 and Iba1 in spinal cord, the immunofluorescence intensity of CSF-1 in DRG and Iba1 in spinal cord , and the expression of TNF-α, IL-6 and IL-1β in spinal cord were significantly up-regulated in CINP group(P<0.01, P<0.001). Compared with CINP group, the protein expression of CSF-1 in DRG and spinal cord, the protein and mRNA expression of Iba1 in spinal cord, the immunofluorescence intensity of spinal Iba1 and CSF-1 in DRG, and the expression of TNF-α, IL-6 and IL-1β were obviously downregulated in CINP+anti group(P<0.05, P<0.01, P<0.001) . 【Conclusion】 The transport of CSF-1 from dorsal root ganglion to spinal cord is involved in the process of neuropathic pain induced by vincristine, and its mechanism may be related to the activation of microglia and inflammatory reaction in rat spinal cord.

The incidence of metabolic rheumatism gout has been increasing with a trend of more younger patients and atypical symptoms. Typical gout is easy to be diagnosed, but it is difficult for atypical cases. Finding uric acid crystal in articular fluid by polarizing light microscope is a gold standard of diagnosis, but it is an invasive diagnostic method and difficult to be widely used. The patients need further imaging examination for assistance of diagnosis and guide of follow-up treatment. This article reviews the research progress of different imaging methods used for diagnosis of gouty arthritis.

Objective: To evaluate the role of 2B-containing NMDA receptors (NR2B) in sevoflurane anesthesia-induced cognitive dysfunction in aged rats. Methods: Thirty-two healthy male Sprague-Dawley rats, aged 18 months, weighing 570-630 g, were divided into 4 groups (n=8 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S), sevoflurane anesthesia plus NR2B specific inhibitor Ro 25-6981 group (group S+ RO) and Ro 25-6981 group (group RO). S and S+ RO groups inhaled 3% sevoflurane for 4 h. Ro 25-6981 1 mg/kg was intraperitoneally injected at 15 min before inhaling sevoflurane in group S+ RO.Morris water maze test was performed at 2 days after the end of anesthesia to assess cognitive function.The rats were then sacrificed, and hippocampal tissues were obtained for determination of the expression and phosphorylation of ERK1/2 by Western blot. Results: Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was reduced, the time of staying at the original platform quadrant was shortened, and the phosphorylation of ERK1/2 was decreased in group S (P<0.05), and no significant change was found in the escape latency in S+ RO and RO groups (P>0.05). Compared with group S, the escape latency was significantly shortened, the frequency of crossing the original platform was increased, the time of staying at the original platform quadrant was prolonged, and the phosphorylation of ERK1/2 was increased in group S+ RO(P<0.05). There was no significant difference in ERK1/2 expression among the four groups (P>0.05). Conclusion The mechanism by which sevoflurane anesthesia induces cognitive dysfunction is related to up-regulating the expression of NR2B and inhibiting the activity of ERK1/2 in aged rats.