Adjuvant Therapy-Free Strategy for Stage IB to IIIA Non-Small-Cell Lung Cancer Patients After Radical Resection Based on Longitudinal Undetectable Molecular Residual Disease: Prospective, Multicenter, Single-Arm Study (CTONG 2201).

BACKGROUND: The utility of circulating tumor DNA to monitor molecular residual disease (MRD) has been clinically confirmed to predict disease recurrence in non-small cell lung cancer (NSCLC) patients after radical resection. Patients with longitudinal undetectable MRD show a favorable prognosis and might not benefit from adjuvant therapy. PATIENTS AND METHODS: The CTONG 2201 trial is a prospective, multicenter, single-arm study (ClinicalTrials.gov identifier, NCT05457049), designed to evaluate the hypothesis that no adjuvant therapy is needed for patients with longitudinal undetectable MRD. Pathologically confirmed stage IB-IIIA NSCLC patients who have undergone radical resection will be screened. Only patients with 2 consecutive rounds of undetectable MRD will be enrolled (first at days 3-10, second at days 30 ± 7 after surgery), and admitted for imaging and MRD monitoring every 3 months without adjuvant therapy. The primary endpoint is the 2-year disease-free survival rate for those with longitudinal undetectable MRD. The recruitment phase began in August 2022 and 180 patients will be enrolled. CONCLUSIONS: This prospective trial will contribute data to confirm the negative predictive value of MRD on adjuvant therapy for NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT05457049 (CTONG 2201).

An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.

BACKGROUND: Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown. METHODS: Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining. RESULTS: OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin-proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels. CONCLUSIONS: These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC. Video Abstract.

Characteristics of amino acid metabolism in preterm infants in Guangxi, China. / å¹¿è¥¿åœ°åŒºæ—©äº§å„¿æ°¨åŸºé ¸ä»£è°¢ç‰¹ç‚¹ç ”ç©¶.

OBJECTIVES: To study the characteristics of amino acid metabolism in preterm infants in Guangxi, China. METHODS: A retrospective analysis was performed on the medical data of 30 757 neonates who underwent the screening for inherited metabolic diseases and had negative results in Guangxi Neonatal Disease Screening Center from 2018 to 2020. Among these neonates, there were 28 611 normal full-term infants (control group) and 2 146 preterm infants (preterm birth group). According to gestational age, the preterm infants were further divided into four groups: very preterm (n=209), moderately preterm (n=307), and late preterm group (n=1 630). According to birth weight, they were divided into three groups: very low birth weight group (n=161), low birth weight group (n=1 085), and normal birth weight group (n=900). According to blood collection time, they were divided into three groups: 3-7 days group (n=1 664), 8-14 days group (n=314) and 15-28 days group (n=168). Tandem mass spectrometry was performed to measure the levels of 11 amino acids in dried blood spots, which were then compared between groups. RESULTS: After adjustment for confounding factors, there were significant differences in the levels of 11 amino acids among different gestational age groups (P<0.05), and significant differences were observed in the levels of the 11 amino acids between the control group and the various preterm groups (except for citrulline and methionine in the late preterm group). There were significant differences in the levels of 11 amino acids among different birth weight groups (P<0.05). Except for ornithine, there were significant differences in the levels of other amino acids among the different blood collection time groups (P<0.05). CONCLUSIONS: Gestational age, birth weight and blood collection time all affect amino acid metabolism in preterm infants in Guangxi, China. This provides a basis for the laboratory to establish the reference standard and clinical interpretation of blood amino acid levels in preterm infants, and to improve the nutritional metabolism of preterm infants.

[Revealing characteristics and rules of acupoint sensitization phenomena: based on knee osteoarthritis].

OBJECTIVE: To explore the characteristics and rules of acupoint sensitization phenomena based on knee osteoarthritis (KOA), one of the clinical dominant diseases of acupuncture-moxibustion. METHODS: In combination with literature and expert experiences, the acupoints with the highest use frequency in treatment of KOA were screened, e.g. Heding (EX-LE 2), Liangqiu (ST 34), Mingmen (GV 4), Neixiyan (EX-LE 4), Ququan (LR 8) and Dubi (ST 35). In 814 patients with KOA and 217 healthy subjects, the acupoint temperature, mechanic pain threshold and pressure pain threshold were detected separately. Using machine learning method, the sensitization was judged at each acupoint. RESULTS: Compared with healthy subjects, the acupoint temperature was increased and the mechanic pain threshold and pressure pain threshold were reduced in KOA patients (P<0.05). Besides, the cut-off value was presented to distinguish whether the acupoint was sensitized or not. The results of machine learning showed that the highest prediction accuracy of acupoint sensitization was 86.7% (Shenshu [BL 23]) and the lowest one was 73.9% (Heding [EX LE 2]). The prediction accuracy at the third clinical stage trial was higher, the highest was 93.3% (Ququan [LR 8]) in KOA patients. CONCLUSION: It is confirmed that the acupoint sensitization reflects the characteristics of disease and is correlative with the conditions of illness, which may provide the reference for the auxiliary diagnosis and condition assessment of KOA.

Infection with Trypanosoma lewisi or Trypanosoma musculi may promote the spread of Toxoplasma gondii.

Toxoplasma gondii can infect almost all warm-blooded vertebrates with pathogensis being largely influenced by the host immune status. As important epidemiological hosts, rodents are globally distributed and are also commonly found infected with haemoflagellates, such as those in the genus Trypanosoma. We here address whether and how co-infection with trypanosomes can influence T. gondii infection in laboratory models. Rats of five strains, co-infected with T. lewisi and mice of four strains, co-infected with T. musculi, were found to be more or less susceptible to T. gondii infection, respectively, with corresponding increased or decreased brain cyst burdens. Downregulation of iNOS expression and decreased NO production or reverse were observed in the peritoneal macrophages of rats or mice, infected with trypanosomes, respectively. Trypanosoma lewisi and T. musculi can modulate host immune responses, either by enhancement or suppression and influence the outcome of Toxoplasma infection.

Efficacy, safety and cost-effectiveness of flow diverters in the treatment of intracranial aneurysms / 国际脑血管病杂志

Intracranial aneurysm is a common cerebrovascular disease. Its rupture causes subarachnoid hemorrhage with high mortality and disability. At present, the main treatment methods of intracranial aneurysms include craniotomy clipping and intravascular embolization. With the invention of flow diverters and wide application in clinic, it has gradually become another mainstream treatment method of intracranial aneurysms. This article reviews the effectiveness, safety and cost-effectiveness of flow diverters in the treatment of intracranial aneurysms.

Mechanism of inhibitory effect of interferon and its related signal pathway on the invasion of glioma / 国际肿瘤学杂志

Glioma is a tumor with a high incidence of intracranial tumor. Because of its high degree of malignancy, strong invasiveness and high mortality, the current conventional treatment cannot achieve the desired therapeutic effect, which greatly affects the quality of life of patients. As a protein with the functions of anti-proliferation, anti-angiogenesis and anti-invasion, interferon is widely used in the treatment of all kinds of tumors in clinic. Many studies have shown that interferon plays an important role in the occurrence and development of gliomas. To explore the mechanism of interferon and its related signal pathway in the process of glioma invasion, and to study the new treatment of glioma is very necessary in clinical treatment.

Molecular mechanism of vasculogenic mimicry in brain glioma / 国际肿瘤学杂志

Vasculogenic mimicry (VM) is a new tumor angiogenesis mode independent of endothelial cells and an important component of tumor microcirculation. The formation mechanism of VM in glioma is complex and variable. Various molecules and signal pathways (such as hypoxia induction factor and matrix metalloproteasefamily) interact in the formation process, to jointly regulate the formation of VM. The in-depth study of molecular mechanism can provide a theoretical basis for drug research and development against VM formation.

Signaling pathway of early brain injury after subarachnoid hemorrhage / 国际脑血管病杂志

Early brain injury (EBI) refers to the direct damage and secondary pathophysiological changes of brain tissue within 72 h after aneurysmal subarachnoid hemorrhage. Studies have shown that a variety of signaling pathways are involved in the mechanism of EBI, such as ecoxy chloropropane Kelch sample related protein-1 (Keap1)-nuclear factor E2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, Toll-like receptor 4 (TLR4)/nuclear factor-κB pathway, phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway. This article reviews the mechanisms of action of different signaling pathways involved in EBI.

Signaling pathway of early brain injury after subarachnoid hemorrhage / 国际脑血管病杂志

Early brain injury (EBI) refers to the direct damage and secondary pathophysiological changes of brain tissue within 72 h after aneurysmal subarachnoid hemorrhage.Studies have shown that a variety of signaling pathways are involved in the mechanism of EBI,such as ecoxy chloropropane Kelch sample related protein-1 (Keapl)-nuclear factor E2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway,Toll-like receptor 4 (TLR4)/nuclear factor-κB pathway,phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway.This article reviews the mechanisms of action of different signaling pathways involved in EBI.

Endothelial progenitor cells and acute ischemic stroke / 国际脑血管病杂志

Endothelial progenitor cells (EPCs) are the precursor of vascular endothelial cells and are involved in a variety of biological metabolic processes.This article reviews the roles of EPCs in acute ischemic stroke.

MicroRNA-30a suppresses non-small-cell lung cancer by targeting Myb-related protein B.

Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer mortality worldwide. A growing body of evidence indicates that microRNA (miR) have important and diverse roles in the proliferation, apoptosis and metastasis of human cancer cells. In the present study, the molecular regulation mechanism of miR-30a and its potential target, Myb-related protein B (MYBL2) was investigated in NSCLC. Reverse transcription-quantitative polymerase chain reaction results showed that miR-30a was significantly downregulated in NSCLC tissues compared with adjacent normal tissues (P<0.05). MYBL2 has a putative miR-30a target site in its 3'untranslated region according to previous data, prediction databases and TargetScan software. In the present study, a negative correlation was demonstrated between miR-30a and MYBL2 expression in NSCLC. Direct interaction between miR-30a and MYBL2 was also confirmed via a dual-luciferase reporter assay. miR-30a overexpression inhibited the growth of A549 and H460 cells via MTT and bromodeoxyuridine incorporation assays, whereas miR-30a downregulation promoted cell proliferation. In addition, miR-30a overexpression not only increased cell apoptosis and induced cell cycle arrest in A549 and H460 cell lines, but also attenuated tumor growth, and mRNA and protein expression levels of MYBL2. The present findings suggest that miR-30a may suppress NSCLC by targeting MYBL2.

Oncogenic activity of insulin in the development of non-small cell lung carcinoma.

Insulin is associated with the progression of numerous different types of cancer. However, the association between insulin and non-small cell lung carcinoma (NSCLC) remains unknown. The aim of the present study was to evaluate the role of insulin in the proliferation, migration and drug resistance of NSCLC cells, and to determine whether the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway was involved. NSCLC cells were treated with insulin in the absence or presence of LY294002, an inhibitor of the PI3K/Akt pathway. Following co-incubation with insulin, cell proliferation and drug resistance were measured by MTT; cell migration was examined by wound healing and Transwell assays; and the expression of cyclin A, proliferating cell nuclear antigen (PCNA), p27, matrix metalloproteinase 3 (MMP3), P-gp and proteins involved in the PI3K/Akt pathway were assessed via western blotting. The results of the current study demonstrated that insulin enhanced the proliferation, migration and drug resistance of NSCLC cells. Correspondingly, insulin upregulated the expression of cyclin A, PCNA, MMP3, P-gp and downregulated p27 expression in NSCLC cells. Following treatment with insulin, it was demonstrated that phospho-Akt expression increased in a dose-dependent manner. However, the effects of insulin on NSCLC cells was inhibited by the PI3K/Akt pathway inhibitor LY294002. Therefore, the results of the current study indicate that insulin is associated with the development of NSCLC by activating the PI3K/Akt pathway. This may improve understanding of the mechanism of action of insulin in NSCLC in the future.

Research progress of interferon induced glioma cell apoptosis / 国际肿瘤学杂志

Glioma is a central nervous system tumor,which originates neuroderm and expresses the high malignant degree.Due to the particularity of the usual location,it makes the treatment of glioma difficult to achieve the desired effect.Interferon is a kind of important cytokines,and it has some biological characteristics,such as inducing apoptosis,inhibiting of tumor growth,and pathological angiogenesis,regulating immune function and so on.Studies have shown that there are many key molecules in the interferon signaling pathways,and these molecules play an important role in the occurrence and development of glioma cell apoptosis.Explore the key molecules and its mechanism of action in the process of Interferon inducing glioma,which may provide new clinical strategies for diagnosis and treatment of glioma.

Effect and mechanism of Musashi2 and related signal pathways in genesis and progression of malignant tumor / 国际肿瘤学杂志

In mammals,there are two RNA-binding proteins,Musashi (Msi)1 and Msi2,constituting the Msi family.Msi2 is mainly distributed among neural,hematopoietic,gastrointestinal,pancreatic and epithelial stein cells.It is of great importance to maintain the balance between proliferation and differentiation of stem cells and regulate their growth and development.The changed expression of this protein will induce genesis and progression of malignant tumor through many kinds of signal pathways.Thus,Msi2 is trusted to provide a predictive mark and a therapeutic target for related tumors.

The mechanism of Wnt/β-catenin signaling pathway in glioma invasion / 国际肿瘤学杂志

Invasion of glioma is a complex process with multiple steps and multiple factors,including the inhibition of tumor cell adhesion,the degradation of extracellular matrix,the promotion of tumor cells migration and angiogenesis.The abnormal activation of Wnt/β-catenin signaling pathway is closely related to the invasion of glioma.The study of Wnt/β-catenin pathway affecting invasion mechanism of glioma will provide new ideas and targets for the treatment of glioma.

Behavioral Risk Profile of Men Who Have Sex with Men in Beijing, China: Results from a Cross-sectional Survey with Randomized Response Techniques.

BACKGROUND: Human immunodeficiency virus (HIV) is spreading rapidly among men who have sex with men (MSM) in China. Anonymous questionnaires or direct interviews have been frequently used to study their behavior. The aim of the study was to describe the behavioral risk profile of the MSM in Beijing using the randomized response techniques (RRTs). METHODS: A cross-sectional survey of sexual behavior among a sample of MSM was conducted in two HIV counseling and testing clinics in Beijing. The survey was carried out with an anonymous questionnaire containing sensitive questions on sexual behavior. To obtain the honest responses to the sensitive questions, three distinctive RRTs were used in the questionnaire: (1) Additive randomized response model for quantitative questions, (2) randomized response model for multiple choice questions, and (3) Simmons randomized response model for binomial questions. Formulae for the point estimate, variance, and confidence interval (CI) were provided for each specific model. RESULTS: Using RRTs in a sample of 659 participants, the mean age at first homosexual encounter was estimated to be 21.7 years (95% CI: 21.2-22.2), and each had sex with about three (2.9, 95% CI: 2.4-3.4) male partners on average in the past month. The estimated rate for consistent condom use was 56.4% (95% CI: 50.1-62.8%). In addition, condom was estimated to be used among 80.0% (95% CI: 74.1-85.9%) of the population during last anal sex with a male partner. CONCLUSIONS: Our study employed RRTs in a survey containing questions on sexual behavior among MSM, and the results showed that RRT might be a useful tool to obtain truthful feedback on sensitive information such as sexual behavior from the respondents, especially in traditional Chinese cultural settings.

Comparison of primary coronary percutaneous coronary intervention between Diabetic Men and Women with acute myocardial infarction.

OBJECTIVE: This study aimed to explore the short-term efficacy and safety of primary percutaneous coronary intervention (PCI) in female diabetic patients complicated with acute myocardial infarction (AMI). METHODS: A total of 169 diabetic patients with AMI who underwent primary PCI were selected and divided into group A (52 females) and group B (117 males). The clinical data, characteristics of coronary artery lesions, lengths of hospital stay, and incidences of complications were then compared between two groups. RESULTS: The average age, history of hyperlipidemia, double branch lesions, triple branch lesions, and left main lesions were significantly higher in group A than in group B (P < 0.05). Smoking history, PCI history, and pre-infarction angina were distinctly lower in group A than in group B (P < 0.05). Thrombolysis in myocardial infarction 3 (TIMI3) flow and TIMI myocardial perfusion grade 3 (TMPG3) after PCI were markedly lower in group A than in group B (P < 0.001). Group A had a higher incidence of complications, such as severe arrhythmia, cardiac function Killip III/IV, cardiogenic shock, major, moderate and mild bleed event, as well as a 30-day mortality rate, compared with group B (P < 0.05). CONCLUSION: In summary, our study demonstrated that female diabetic patients with AMI had lower TIMI3 flow and TMPG3 following PCI than male patients, while there was higher incidence of complications and 30-day mortality rate. Therefore, more attention should be paid to the therapy of diabetic women with acute myocardial infarction as well as the control of risk factors.

Resistance to normal human serum reveals Trypanosoma lewisi as an underestimated human pathogen.

Human-infectious trypanosomes such as Trypanosoma cruzi, T. brucei rhodesiense, and T. b. gambiense can be discriminated from those only infecting animals by their resistance to normal human serum (NHS). These parasites are naturally resistant to trypanolysis induced by the human-specific pore-forming serum protein apolipoprotein L1 (ApoL-1). T. lewisi, a worldwide distributed parasite, has been considered as rat-specific and non-pathogenic to the natural hosts. Here we provide evidence that 19 tested T. lewisi isolates from Thailand and China share resistance to NHS. Further investigation on one selected isolate CPO02 showed that it could resist at least 90% NHS or 30 µg/ml recombinant human ApoL-1 (rhApoL-1) in vitro, in contrast to T. b. brucei which could not survive in 0.0001% NHS and 0.1 µg/ml rhApoL-1. In vivo tests in rats also demonstrated that this parasite is fully resistant to lysis by NHS. Together with recent reports of atypical human infection by T. lewisi, these data allow the conclusion that T. lewisi is potentially an underestimated and thus a neglected human pathogen.

Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells.

Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.