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

Objective To evaluate the value of high-throughput sequencing(HTS)data reanalysis that does not include ERBB2 copy number variation(CNV)analysis,in identifying ERBB2 amplification in patients with colorectal cancer.Methods The HTS data of 252 cases of colorectal cancer diagnosed by pathological biopsy who received peripheral blood cfDNA HTS detection samples were retrospectively analyzed.According to the HTS data of ERBB2 non-amplified samples judged by immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH),the number of chromosome 17(Chr17)reads in the total number of reads was calculated the range of the ratio was initially determined as the threshold for prompting ERBB2 amplification.Suspected positive samples were screened according to thresholds and verified by digital PCR,IHC and FISH.Results The proportion of the number of Chr17 reads accounts for the number of total reads in the 89 cases of ERBB2 non-amplified samples determined by IHC and/or FISH ranged from 0.188 to 0.299(0.239±0.192).Using 0.298(1.25 times the mean)as the threshold indicating ERBB2 amplification,the data of 163 samples were analyzed,of which 7 cases were suspected to be positive,and the ratio ranged from 0.302 to 0.853.Among them,5 cases were determined to be positive by IHC and/or FISH,and 6 cases were confirmed to be positive by digital PCR.The ratio of the number of Chr17 reads to the number of total reads was positively correlated with the ratio of ERBB2/EIF2C1,and the correlation was good(r2=0.909).Conclusion The high-throughput sequencing data that does not cover the ERBB2 CNV analysis has a certain hint value for ERBB2 amplification in patients with colorectal cancer.

This article aims to analyze the therapeutic effect and probe into the mechanism of Sanhuang Hushen Fangshuai Decoction in treating chronic kidney disease(CKD) based on metabolomics and bioinformatics. The patients with stage 3-4 CKD diagnosed and treated in the Changzhou Hospital of Traditional Chinese Medicine from June 2023 to March 2024 were enrolled in this study. The patients were treated with Sanhuang Hushen Fangshuai Decoction, and the therapeutic effect was evaluated. The serum samples were collected before and after treatment. Ultra-performance liquid chromatography was employed to detect metabolites in the serum, and multivariate statistical analysis was performed. Bioinformatics was employed to screen the active components and targets of the decoction and the potential targets of CKD. The protein-protein interaction(PPI) network of the common targets shared by the decoction and CKD and the drug-component-target network were constructed. The core components and targets were screened according to the correlation degree of the network. The binding between core components and targets was verified by molecular docking. The results showed that Sanhuang Hushen Fangshuai Decoction improved the renal function and reduced proteinuria. Compared with the healthy population, the post-treatment population showed recovery of 54 up-regulated metabolites and 43 down-regulated metabolites. Enrichment analysis results showed that the key pathways included adenosine triphosphate binding cassette(ABC) transport, tryptophan metabolism, and tyrosine metabolism. The results of bioinformatics analysis showed that the core components of Sanhuang Hushen Fangshuai Decoction in treating CKD included kaempferol, β-sitosterol, luteolin, 7-O-methylisolingol, and tanshinone Ⅱ_A. The core targets included TP53, PTGS2, JUN, AKT1, and TNF. Molecular docking results showed that the core components bound well to the target genes. The results of joint pathway analysis suggested that both differential metabolites and key targets were involved in galactose metabolism, nicotinamide metabolism, and other pathways. This study suggests that Sanhuang Hushen Fangshuai Decoction is effective for CKD, and it can regulate multiple abnormal metabolites and participates in multiple metabolic pathways involving amino acids and sugars. The active components such as kaempferol in the decoction may regulate related targets such as TP53 and PTGS2. This study provides a basis for the prevention and treatment of CKD with traditional Chinese medicine.
Drugs, Chinese Herbal/administration & dosage* ; Renal Insufficiency, Chronic/genetics* ; Humans ; Computational Biology ; Male ; Metabolomics ; Protein Interaction Maps/drug effects* ; Middle Aged ; Molecular Docking Simulation ; Female ; Adult ; Aged

During coronavirus disease 2019 epidemic, the treatment of severe trauma has been impacted. The Consensus on emergency surgery and infection prevention and control for severe trauma patients with 2019 novel corona virus pneumonia was published online on February 12, 2020, providing a strong guidance for the emergency treatment of severe trauma and the self-protection of medical staffs in the early stage of the epidemic. With the Joint Prevention and Control Mechanism of the State Council renaming "novel coronavirus pneumonia" to "novel coronavirus infection" and the infection being managed with measures against class B infectious diseases since January 8, 2023, the consensus published in 2020 is no longer applicable to the emergency treatment of severe trauma in the new stage of epidemic prevention and control. In this context, led by the Chinese Traumatology Association, Chinese Trauma Surgeon Association, Trauma Medicine Branch of Chinese International Exchange and Promotive Association for Medical and Health Care, and Editorial Board of Chinese Journal of Traumatology, the Chinese expert consensus on emergency surgery for severe trauma and infection prevention during coronavirus disease 2019 epidemic ( version 2023) is formulated to ensure the effectiveness and safety in the treatment of severe trauma in the new stage. Based on the policy of the Joint Prevention and Control Mechanism of the State Council and by using evidence-based medical evidence as well as Delphi expert consultation and voting, 16 recommendations are put forward from the four aspects of the related definitions, infection prevention, preoperative assessment and preparation, emergency operation and postoperative management, hoping to provide a reference for severe trauma care in the new stage of the epidemic prevention and control.

OBJECTIVE: To explore the effect of cytokine levels on early death and coagulation function of patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: Routine examination was performed on 69 newly diagnosed APL patients at admission. Meanwhile, 4 ml fasting venous blood was extracted from the patients. And then the supernatant was taken after centrifugation. The concentrations of cytokines, lactate dehydrogenase (LDH) and ferritin were detected by using the corresponding kits. RESULTS: It was confirmed that cerebral hemorrhage was a major cause of early death in APL patients. Elevated LDH, decreased platelets (PLT) count and prolonged prothrombin time (PT) were high risk factors for early death (P <0.05). The increases of IL-5, IL-6, IL-10, IL-12p70 and IL-17A were closely related to the early death of newly diagnosed APL patients, and the increases of IL-5 and IL-17A also induced coagulation disorder in APL patients by prolonging PT (P <0.05). In newly diagnosed APL patients, ferritin and LDH showed a positive effect on the expression of IL-5, IL-10 and IL-17A, especially ferritin had a highly positive correlation with IL-5 (r =0.867) and IL-17A (r =0.841). Moreover, there was a certain correlation between these five high-risk cytokines, among which IL-5 and IL-17A (r =0.827), IL-6 and IL-10 (r =0.823) were highly positively correlated. CONCLUSION Elevated cytokine levels in newly diagnosed APL patients increase the risk of early bleeding and death. In addition to the interaction between cytokines themselves, ferritin and LDH positively affect the expression of cytokines, thus affecting the prognosis of APL patients.
Humans ; Leukemia, Promyelocytic, Acute/diagnosis* ; Cytokines/metabolism* ; Interleukin-10 ; Interleukin-17/metabolism* ; Interleukin-6/metabolism* ; Interleukin-5/metabolism* ; Blood Coagulation Disorders ; Ferritins ; Tretinoin

Objective: To investigate the clinicopathological features, treatment and prognosis of gastric intermediate-risk gastrointestinal stromal tumor (GIST), so as to provide a reference for clinical management and further research. Methods: A retrospective observational study of patients with gastric intermediate-risk GIST, who underwent surgical resection between January 1996 and December 2019 at Zhongshan Hospital of Fudan University, was carried out. Results: Totally, 360 patients with a median age of 59 years were included. There were 190 males and 170 females with median tumor diameter of 5.9 cm. Routine genetic testing was performed in 247 cases (68.6%, 247/360), and 198 cases (80.2%) showed KIT mutation, 26 cases (10.5%) showed PDGFRA mutation, and 23 cases were wild-type GIST. According to "Zhongshan Method"(including 12 parameters), there were 121 malignant and 239 non-malignant cases. Complete follow-up data were available in 241 patients; 55 patients (22.8%) received imatinib therapy, 10 patients (4.1%) experienced tumor progression, and one patient (PDGFRA mutation, 0.4%) died. Disease-free survival (DFS) and overall survival rate at 5 years was 96.0% and 99.6%, respectively. Among the intermediate-risk GIST, there was no difference in DFS between the overall population, KIT mutation, PDGFRA mutation, wild-type, non-malignant and malignant subgroups (all P>0.05). However, the non-malignancy/malignancy analysis showed that there were significant differences in DFS among the overall population (P<0.01), imatinib treatment group (P=0.044) and no imatinib treatment group (P<0.01). Adjuvant imatinib resulted in potential survival benefit for KIT mutated malignant and intermediate-risk GIST in DFS (P=0.241). Conclusions: Gastric intermediate-risk GIST shows a heterogeneous biologic behavior spectrum from benign to highly malignant. It can be further classified into benign and malignant, mainly nonmalignant and low-grade malignant. The overall disease progression rate after surgical resection is low, and real-world data show that there is no significant benefit from imatinib treatment after surgery. However, adjuvant imatinib potentially improves DFS of intermediate-risk patients with tumors harboring KIT mutation in the malignant group. Therefore, a comprehensive analysis of gene mutations in benign/malignant GIST will facilitate improvements in therapeutic decision-making.
Male ; Female ; Humans ; Middle Aged ; Gastrointestinal Stromal Tumors/surgery* ; Retrospective Studies ; Antineoplastic Agents/therapeutic use* ; Prognosis ; Imatinib Mesylate/therapeutic use* ; Mutation ; Proto-Oncogene Proteins c-kit/genetics*

OBJECTIVES: To establish an LC-MS/MS method based on single hair micro-segmental technique, and verify the detection of 42 psychoactive substances in 0.4 mm hair segments. METHODS: Each piece of single hair was cut into 0.4 mm segments and extracted by sonication and the segments were immersed in dithiothreitol-containing extraction medium. Mobile phase A was the aqueous solution containing 20 mmol/L ammonium acetate, 0.1% formic acid, and 5% acetonitrile. Mobile phase B was acetonitrile. An electrospray ionization source in positive ion mode was used for data acquisition in multiple reaction monitoring (MRM) mode. RESULTS: The 42 psychoactive substances in hair had a good linear relationship within their respective linear ranges (r>0.99), the limits of detection were 0.2-10 pg/mm, the limits of quantification were 0.5-20 pg/mm, the intra-day and inter-day precisions were 1.5%-12.7%, the intra-day and inter-day accuracies were 86.5%-109.2%, the recovery rates were 68.1%-98.2%, and the matrix effects were 71.3%-111.7%. The method was applied to hair samples collected from one volunteer at 28 d after a single dose of zolpidem, with zolpidem detected in 5 hairs was 1.08-1.60 cm near the root tip, and the concentration range was 0.62-20.5 pg/mm. CONCLUSIONS The micro-segmental technique of single hair analysis can be applied to the investigation of drug-facilitated sexual assault cases.
Humans ; Chromatography, Liquid/methods* ; Zolpidem ; Tandem Mass Spectrometry/methods* ; Hair ; Acetonitriles ; Chromatography, High Pressure Liquid

Aim To study the effect of G protein-coupled estrogen receptor(GPER)inhibitor G15 on the sensitivity of breast cancer tamoxifen-resistant cells to T-47DTR. Methods Experiments were carried out with 4-hydroxytamoxifen(4-OHT),the active form of tamoxifen in vivo. The sensitivity of tamoxifen-resistant breast cancer cell line T-47DTR and its parental cell line T-47D to tamoxifen was detected by MTT assay; the expression of GPER protein was analyzed by plasma separation of inhibitor G15; the effect of 4-OHT combined with G15 on the apoptosis of T-47DTR cells was analyzed by flow cytometry AnnexinV-FITC/PI double staining; the expression levels of apoptosis-related proteins Bax,Bcl-2,caspase-3,cleaved caspase-3,caspase-9,cleaved caspase-9 were analysed by Western blot. Results(1)Compared with the parental cell T-47D,the resistance of T-47DTR-resistant cells to 4-OHT was significantly enhanced.(2)When 4-OHT(2 μmol·L-1)was administered,the membrane distribution of GPER increased,indicating that GPER was activated in T-47DTR-resistant cells compared with the control group; Compared with OHT,the use of G15(5 μmol·L-1)and OHT significantly reduced the expression of GPER.(3)GPER inhibitor G15 could increase the apoptotic rate of T-47DTR-resistant cells while down-regulating the anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic proteins Bax,cleaved caspase-3,cleaved caspase-9. Conclusions The GPER inhibitor G15 increases the apoptosis of T-47DTR cells and restores the sensitivity of drug-resistant cells to tamoxifen.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Objective:To investigate the ability and current situation of nursing undergraduates to use social media for health education, and analyze the impact of social media health education experience on the ability of nursing undergraduates to use social media, so as to provide reference information for the design of nursing undergraduates' health education courses in the future.Methods:Using the convenient sampling method,from May to September 2019, 147 nursing undergraduates from four medical colleges in Beijing were selected, and the general information questionnaire and the Chinese version of Social Media Competency Inventory were used for the questionnaire survey. Using the objective sampling method, the 20 nursing undergraduates were selected for semi-structured interview.Results:57.14%(84/147) of nursing undergraduates had used social media for health education at the undergraduate stage. Among the scores of all dimensions of social media ability, the scores of social media self-efficacy (4.42 points per item) and performance expectation (3.31 points per item) were higher. In the interview, nursing undergraduates believed that after college training, the ability of using publicity tools and making carriers, the ability of information selection and transmission, the ability of teamwork and other social media applications were improved.Conclusions:The current situation of applying social media to health education for nursing undergraduates needs to be further improved, and the ability of applying social media to health education has great room for improvement. Social media health education experience can effectively improve their abilities related to social media application.It is suggested that the relevant courses and training of applying social media to health education should be promoted in undergraduate nursing education in Colleges and universities.