Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Background/Aims: The performance of machine learning (ML) in predicting the outcomes of patients with hepatocellular carcinoma (HCC) remains uncertain. We aimed to develop risk scores using conventional methods and ML to categorize early-stage HCC patients into distinct prognostic groups. Methods: The study retrospectively enrolled 1,411 consecutive treatment-naïve patients with the Barcelona Clinic Liver Cancer (BCLC) stage 0 to A HCC from 2012 to 2021. The patients were randomly divided into a training cohort (n=988) and validation cohort (n=423). Two risk scores (CATS-IF and CATS-INF) were developed to predict overall survival (OS) in the training cohort using the conventional methods (Cox proportional hazards model) and ML-based methods (LASSO Cox regression), respectively. They were then validated and compared in the validation cohort. Results: In the training cohort, factors for the CATS-IF score were selected by the conventional method, including age, curative treatment, single large HCC, serum creatinine and alpha-fetoprotein levels, fibrosis-4 score, lymphocyte-tomonocyte ratio, and albumin-bilirubin grade. The CATS-INF score, determined by ML-based methods, included the above factors and two additional ones (aspartate aminotransferase and prognostic nutritional index). In the validation cohort, both CATS-IF score and CATS-INF score outperformed other modern prognostic scores in predicting OS, with the CATSINF score having the lowest Akaike information criterion value. A calibration plot exhibited good correlation between predicted and observed outcomes for both scores. Conclusions Both the conventional Cox-based CATS-IF score and ML-based CATS-INF score effectively stratified patients with early-stage HCC into distinct prognostic groups, with the CATS-INF score showing slightly superior performance.

Humans ; Child ; Klinefelter Syndrome/complications* ; Lupus Erythematosus, Systemic/complications*

The present study investigated the effect of active components of Descurainia sophia on allergic asthma and explored the underlying mechanism. SD male rats were randomly divided into a normal group(NC), a model group(M), a D. sophia decoction group(DS), a D. sophia fatty oil group(FO), a D. sophia flavonoid glycoside group(FG), a D. sophia oligosaccharide group(Oli), and a positive drug dexamethasone group(Y). The allergic asthma model was induced in rats by intraperitoneal injection of ovalbumin(OVA) and aluminum hydroxide gel adjuvant(sensitization) and atomization of OVA solution(excitation). After modeling, asthma-related indicators, tracheal phenol red excretion, inflammatory cell levels in the peripheral blood, lung permeability index(LPI), and oxygenation index(OI) of rats were detected. The pathological changes of lung tissues were observed by HE staining. Enzyme-linked immunosorbent assay(ELISA) was used to detect the content of inflammatory factors immunoglobulin E(IgE), interleukin-4(IL-4), and interferon-γ(IFN-γ) in the bronchoalveolar lavage fluid(BALF) and the content of endothelin-1(ET-1) and angiotensin-converting enzyme(ACE) in lung tissue homogenate. The serum content of nitric oxide(NO) was detected by colorimetry. Western blot was employed to determine the protein expression of Toll-like receptor 4(TLR4), nuclear factor κB-p65(NF-κB-p65), phosphorylated NF-κB-p65(p-NF-κB-p65), myosin light chain kinase(MLCK), vascular endothelial cadherin(VE cadherin), connexin 43, and claudin 5, and the mechanism of active components of D. sophia on allergic asthma was explored. As revealed by the results, the M group showed extensive infiltration of inflammatory cells around the bronchus of the lung tissues of the allergic asthma rats, thickened bronchial wall, severely deformed alveolar structure, increased number of wheezes, the content of IgE, IL-4, ET-1, and ACE, inflammatory cells, and LPI, and reduced latency of asthma, tracheal phenol red excretion, IFN-γ, NO content, and OI. After the intervention of the active components of D. sophia, the DS, FO, FG, Oli, and Y groups showed improved asthma-related indicators, tracheal phenol red excretion, and lung tissue lesions in allergic asthma rats, and the effects in the FO and Oli groups were superior. The content of inflammatory factors in BALF was recovered in the DS, FO, and Y groups and the FG and Oli groups. The number of inflammatory cells in rats was reduced in the DS and FO groups, and the FG, Oli, and Y groups to varying degrees, and the effect in the FO group was superior. DS, FO, Oli, and Y reduced ET-1, ACE, and LPI and increased NO and OI. FG recovered NO, ET-1, ACE, LPI, and OI to improve lung epithelial damage and permeability. Further investigation of inflammation-related TLR4/NF-κB pathways, MLCK, and related skeleton protein levels showed that TLR4, NF-κB-p65, p-NF-κB-p65, and MLCK levels were increased, and VE cadherin, connexin 43, and claudin 5 were reduced in the M group. DS, FO, FG, Oli, and Y could reduce the protein expression related to the TLR4 pathway to varying degrees, and regulate the protein expression of MLCK, VE cadherin, connexin 43, and claudin 5. It is inferred that the active components of D. sophia improve lung permeability in rats with allergic asthma presumedly by regulating the TLR4/NF-κB signaling pathway to improve airway inflammation, mediating MLCK and connexin, and regulating epithelial damage.
Animals ; Asthma/drug therapy* ; Bronchoalveolar Lavage Fluid ; Inflammation/metabolism* ; Lung ; Male ; Permeability ; Rats

Objective: This study aimed to explore the prognostic value of the revised international prognostic scoring system (IPSS-R) and the WHO prognostic scoring system (WPSS) in patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: The clinical data of 184 patients with MDS who received allo-HSCT from July 2016 to June 2019 were retrospectively analyzed. IPSS-R and WPSS were performed at diagnosis and before transplantation. The prognostic values of IPSS-R and WPSS and potential risk factors were explored. Results: With a median follow-up of 21.9 (0.5-47.5) months, the two-year overall survival (OS) and progression-free survival (PFS) rates were (75.1±3.4)% and (71.6±3.6)% , respectively. The two-year cumulative relapse rate and nonrelapse mortality rate were (11.9±0.1)% and (16.5±0.1)% , respectively. There were no significant differences in OS and PFS between the IPSS-R ≤3.5 and >3.5 groups at diagnosis (P=0.409; P=0.724). No significant differences in OS and PFS between the WPSS ≤2 and >2 groups (P=0.426; P=0.726) were observed as well. When the patients were reevaluated before transplantation, the OS and PFS of the IPSS-R ≤3.5 group were significantly better than >3.5 group [OS: (88.6±4.1)% vs (65.8±5.3)% , P=0.003; PFS: (87.6±4.2)% vs (60.5±5.8)% , P=0.002]. However, there were no significant differences in OS and PFS among the WPSS ≤2 and >2 groups (P=0.584; P=0.565). In addition, the OS and PFS of the improved group based on IPSS-R were significantly better than those of the unimproved group before transplantation [OS: (83.8±4.6)% vs (69.3±5.8)% , P=0.027; PFS: (82.8±4.4)% vs. (64.0±7.2)% , P=0.006]. Multivariate analysis indicated that a pretransplant IPSS-R of >3.5 (P=0.021, HR=2.510, 95% CI 1.151-5.476) and TP53 mutation (P=0.047, HR=2.460, 95% CI 1.014-5.971) were independent risk factors for OS, whereas a pretransplant IPSS-R of >3.5 (P=0.017, HR=2.457, 95% CI 1.175-5.141) and pretransplant cytogenetic poor and very poor (P=0.008, HR=2.765, 95% CI 1.305-5.856) were independent risk factors for PFS. Conclusion: A pretransplantation evaluation of IPSS-R could help determine the prognosis of patients with MDS undergoing allo-HSCT. In addition, patients with improved IPSS-R scores before undergoing allo-HSCT had a better prognosis.
Hematopoietic Stem Cell Transplantation ; Humans ; Myelodysplastic Syndromes/therapy* ; Prognosis ; Retrospective Studies ; Risk Factors

OBJECTIVE: The individual cascades of the insulin-like growth factor-1 (IGF-1) signaling pathway and the molecular mechanism of aging have not been fully clarified. In the current study, we explored the effect of DNA polymerase delta 1 (POLD1) on the IGF-1 signaling pathway in cell aging. METHODS: First, we analyzed the relationship between IGF-1 and POLD1 expression in aging. To investigate the effect of IGF-1 on POLD1 expression and aging, the 2BS cells were incubated with young-age or old-age human serum, IGF-1 protein, or linsitinib. Next, the effect of IGF-1 on aging was examined in the 2BS cells with increased or decreased POLD1 expression to clarify the molecular mechanism. RESULTS: In this study, we found that IGF-1 expression increased and POLD1 expression decreased with aging in human serum and hippocampal tissues of SAMP8 mice, and a negative relationship between IGF-1 and POLD1 expression was observed. Furthermore, the cells cultured with old-age human serum or IGF-1 showed lower POLD1 expression and more pronounced senescence characteristics, and the effect could be reversed by treatment with linsitinib or overexpression of POLD1, while the effect of linsitinib on cell aging could be reversed with the knockdown of POLD1. CONCLUSION Taken collectively, our findings demonstrate that IGF-1 promotes aging by binding to IGF-1R and inhibiting the expression of POLD1. These findings offer a new target for anti-aging strategies.
Humans ; Animals ; Mice ; Insulin-Like Growth Factor I/pharmacology* ; Cellular Senescence ; Aging ; Hippocampus ; DNA Polymerase III

Objective:To evaluate the efficacy and long-term effect of functional electrical stimulation (FES) on cerebral palsy. Methods:Literature retrieval was carried out in the electronic databases of PubMed, Embase, Web of Science, Cochrane Library, China Biology Medicine Disc (CBM), CNKI, Wanfang Database and VIP. The time limit was from the establishment of these databases to March 26th, 2020. According to the inclusion and exclusion criteria, randomized controlled trials about FES for children with cerebral palsy were included. At least two evaluators extracted the data independently and used Cochrane 5.1.0 bias risk assessment tool to evaluate the quality of included studies. The data was analyzed with Review Manager 5.3 software. Results:A total of eleven studies with 513 children were included. The Gross Motor Function Measure-88 (GMFM-88) D/E scores (MD = 8.14, 95%CI 6.26 to 10.02, P < 0.001), GMFM-88 B score (MD = 8.77, 95%CI 4.00 to 13.53, P < 0.001), modified Ashworth Scale (MAS) score (MD = -1.05, 95%CI -1.25 to -0.84, P < 0.001), Kyphosis angle (MD = -10.67, 95%CI -12.21 to -9.13, P < 0.001), Cobb's angle (MD = -2.66, 95%CI -3.38 to -1.93, P < 0.001), step length (MD = 3.35, 95%CI 1.81 to 4.90, P < 0.001), walking speed (MD = 0.09, 95%CI 0.05 to 0.14, P < 0.001) and GMFM score at six weeks follow-up (MD = 4.84, 95%CI 1.90 to 7.77, P = 0.001) were better in FES group than in the control group. There was no significant difference in MAS score between two groups after six weeks of follow-up (MD = 0.04, 95%CI -0.30 to 0.37, P = 0.84). Conclusion:FES could improve the lower-limb and trunk function of children with cerebral palsy, however, the long-term effect of relieving muscle spasm was not significant.

Objective:To investigate the clinical features of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis misdiagnosed as mental disorder, improve the early diagnosis rate and reduce misdiagnosis.Methods:The clinical data of patients with anti-NMDA receptor encephalitis diagnosed at the First Affiliated Hospital of Zhengzhou University from 2012 to 2018 were collected. Patients misdiagnosed as mental disorders were screened out. Their psychiatric symptom characteristics, disease course characteristics, imaging and laboratory findings, treatment and prognosis were retrospectively analyzed.Results:A total of 121 cases of anti-NMDA receptor encephalitis were collected, and 43 cases of mental disorders were screened out. Sixteen of the 43 patients (37.2%) had prodromal symptoms, and all the patients had psychiatric behavioral abnormalities (100%), including 32 cases (74.4%) of seizures, 13 cases (30.2%) of decreased level of consciousness, 21 cases (48.8%) of involuntary movements, 15 cases (34.9%) of decreased memory, 8 cases (18.6%) of speech dysfunction, and 8 cases (18.6%) of other neurological symptoms (central hyperventilation, autonomic dysfunction). Memory loss was observed in 15 cases (34.9%), speech dysfunction in 8 cases (18.6%), other neurological symptoms (central hypoventilation, autonomic dysfunction) in 8 cases (18.6%), and various symptoms may appear simultaneously or successively in the same patient. Thirty-eight cases had complete resolution of symptoms or only minor physical impairment, and 5 cases had recurrent admissions with mental abnormalities and seizures. The recurrence rate accounted for 11.6% (5/43).Conclusions:The clinical manifestations of anti-NMDA receptor encephalitis are complex and varied. Most of them have mental behavior abnormalities as the first symptom, which is easily misdiagnosed as mental disorder and delayed treatment will lead to prolonged disease course and poor prognosis.

With the dropping process of Xuesaitong Dropping Pills(XDP) as the study object, critical factors affecting the quality indicators of pill pass rate, average weight of drop pills and roundness were screened out, so as to deepen the understanding of the dropping process. The critical process units, critical quality attributes and potential critical process influencing factors of XDP were determined by risk analysis and prior knowledge, and then the critical influencing factors were screened out by Plackett-Burman design. First, according to the risk assessment, the critical technique of XDP preparation process was dropping, and then the critical quality attributes of dropping process were pill pass rate, average weight of drop pills and roundness. Then, according to fishbone diagram and failure mode and effects analysis(FMEA), potential critical influencing factors were determined as flow rate, matrix ratio, solid-liquid ratio, feed-liquid temperature, top temperature of condensate, bottom temperature of condensate and dropping distance. Finally, among these seven potential factors, the critical influencing factors were determined as material liquid ratio, dropping distance, top temperature of condensate, bottom temperature of condensate. This study revealed the potential of Plackett-Burman design in screening and understanding the influence of selected factors on XDP dropping process, which could provide a reference for studying the dropping process.
Drugs, Chinese Herbal ; Saponins ; Temperature

Whether in the West or the East, the connection between the ear and the rest of the body has been explored for a long time. Especially in the past century or more, the relevant theoretical and applied research on the ear has greatly promoted the development of ear therapy, and finally the concept of transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed. The purpose of taVNS is to treat a disease non-invasively by applying electrical current to the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear. In the past two decades, taVNS has been a topic of basic, clinical, and transformation research. It has been applied as an alternative to drug treatment for a variety of diseases. Based on the rapid understanding of the application of taVNS to human health and disease, some limitations in the development of this field have also been gradually exposed. Here, we comprehensively review the origin and research status of the field.