Interleukin-1 receptor associated kinase 4 (IRAK-4), acting as a serine threonine kinase, is considered as a key signal node for the transduction of IL-1R family and TLRs signal pathway. Studies have found that IRAK-4 has a hand in many signal pathways, involving the inflammatory response of human joints, intestines, liver and nervous system, as well as other autoimmune diseases. It is also one of the causes of drug resistance of some cancer cells. Therefore, IRAK-4 tends to be an effective therapeutic target for inflammatory diseases and cancer. The prospects for the development of drugs in this pathway is to develop novel IRAK-4 small molecule inhibitors and investigate their safety and effectiveness, enrich the clinical treatment of inflammatory and cancer diseases finally. This paper classified and summarized the latest research progress on small molecule inhibitors of IRAK-4 signaling pathway according to structures of the compounds, in order to provide assistances and references for the research and development of related drugs.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most lethal malignancies worldwide. A novel Chinese medicine formula-01 (NCHF-01) has shown significant clinical efficacy in the treatment of NSCLC, but the mechanism of this formula in the treatment of NSCLC is not fully understood. The aim of this study is to investigate the molecular mechanism of NCHF-01 in inhibiting NSCLC. METHODS: Lewis lung cells (LLC) tumor bearing mice were established to detect the tumor inhibitory effect of NCHF-01. The morphological changes of tissues and organs in LLC tumor-bearing mice were detected by hematoxylin-eosin (HE) staining. NSCLC cells were treated by NCHF-01. The effects of cell viability and proliferation were detected by MTT and crystal violet staining experiment. Flow cytometry was used to detect cell cycle, apoptosis and reactive oxygen species (ROS). Network pharmacology was used to predict the mechanism of its inhibitory effect of NSCLC. Western blot and immunohistochemistry (IHC) were used to detect the expression of related proteins. RESULTS: NCHF-01 can inhibit tumor growth in LLC tumor-bearing mice, and has no obvious side effects on other tissues and organs. NCHF-01 could inhibit cell viability and proliferation, induce G2/M phase arrest and apoptosis, and promote the increase of ROS level. Network pharmacological analysis showed that NCHF-01 exerts anti-NSCLC effects through various biological processes such as oxidative stress and central carbon metabolism. NCHF-01 can reduce the protein expression and enzyme activity of the key enzymes 6-phosphate glucose dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP). CONCLUSIONS NCHF-01 can inhibit NSCLC through oxidative stress dependent on the PPP.
Animals ; Mice ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Reactive Oxygen Species/therapeutic use* ; Medicine, Chinese Traditional ; Pentose Phosphate Pathway ; Oxidative Stress ; Cell Line, Tumor ; Cell Proliferation ; Apoptosis

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.
Bronchopulmonary Dysplasia/epidemiology* ; Female ; Gestational Age ; Humans ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; Pregnancy ; Respiratory Distress Syndrome, Newborn/epidemiology* ; Retrospective Studies ; Treatment Outcome

OBJECTIVE: To analyze the clinical characteristics and long-term prognosis of patients with primary bone lymphoma (PBL). METHODS: The clinical data of 21 patients with PBL treated in our center from 2005 to 2018 were analyzed retrospectively, the clinical characteristics and the factors affecting prognosis of the patients were analyzed. RESULTS: The median age of all the 21 newly diagnosed PBL patients was 40(12-71) years old. Ostealgia was the initial symptom in most of the patients (19/21,90.5%). 42.9%(9/21) of the patients showed single bone lesion only. 571% (12/21) of the patients showed diffuse large B cell lymphoma. 28.6% (6/21) of the patients showed anaplastic large cell lymphoma and 9.5% (2/21) of the patients showed T cell lymphoblastic lymphoma. All the patients received chemotherapy (CHOP or CHOP like regimen, 33.3% plus rituximab) with or without radiotherapy and/or autologous hematopoietic stem cell transplantation (ASCT). 18 patients achieved clinical remission (including 15 for CR and 3 for PR). The median follow-up time was 48 months. The 5-year overall survival rate and progression-free survival rate of the patients were was 67.5% and 63.7%, respectively. The single factors analysis showed that ASCT was the important prognostic factor of PFS, while the single or multiple bone lesion was the factors affecting OS of the patients. There were no statistical differences with the effects of age, sex, stage, ECOG score, LDH level, B symptoms and radiotherapy for the prognosis of patients. CONCLUSION Diffuse large B cell lymphoma is the most common pathological type of PBL. Chemotherapy is the main treatment, which can be combined with radiotherapy and/or ASCT. The ASCT and the number of bone lesion are the factors for long time survival of the patients.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Cyclophosphamide ; Disease-Free Survival ; Doxorubicin ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Middle Aged ; Prednisone ; Prognosis ; Retrospective Studies ; Rituximab/therapeutic use* ; Transplantation, Autologous ; Vincristine

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.
Chemotherapy, Adjuvant ; Female ; Gastrectomy ; Humans ; Male ; Neoadjuvant Therapy ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/surgery*

Objective: To observe the incidence and treatment of radiation rectal injury complicated with anxiety, depression and somatic symptom disorder. Methods: A cross-sectional survey research method was carried out. Patients with radiation rectal injury managed by members of the editorial board of Chinese Journal of Gastrointestinal Surgery were the subjects of investigation. The inclusion criteria of the survey subjects: (1) patients suffered from pelvic tumors and received pelvic radiotherapy; (2) colonoscopy showed inflammatory reaction or ulcer in the rectum. Exclusion criteria: (1) patient had a history of psycho-somatic disease before radiotherapy; (2) patient was unable to use a smart phone, unable to read and understand the questions in the questionnaire displayed on the phone; (3) patient refused to sign an informed consent form. According to the SOMA self-rating scale, PHQ-15 self-rating scale, GAD-7 and PHQ-9 self-rating scale, the electronic questionnaire of "Psychological Survey of Radiation Proctitis" was designed. The questionnaire was sent to patients with radiation rectal injury managed by the committee through the WeChat group. Observational indicators: (1) radiation rectal injury symptom assessment: using SOMA self-rating scale, radiation rectal injury symptom classification: mild group (≤3 points), moderate group (4-6 points) and severe group (> 6 points); (2) incidence of anxiety, depression and physical disorder: using GAD-7, PHQ-9 and PHQ-15 self-rating scales respectively for assessment; (3) correlation of radiation rectal injury symptom grading with anxiety, depression, and somatic symptom disorder. Results: Seventy-one qualified questionnaires were collected, of which 41 (56.9%) were from Guangzhou. Among the 71 patients, 6 were males and 65 were females; the mean age was (55.7±9.3) years old and 48 patients (67.6%) were less than 60 years old; the median confirmed duration of radiation rectal injury was 2.0 (1.0, 5.0) years. (1) Evaluation of symptoms of radiation rectal injury: 18 cases of mild (25.4%), 27 cases of moderate (38.0%), and 26 cases of severe (36.6%). (2) Incidence of anxiety, depression and somatic disorder: 12 patients (16.9%) without comorbidities; 59 patients (83.1%) with anxiety, depression, or somatic disorder, of whom 2 patients only had anxiety, 1 patient only had depression, 9 only had somatic disorder, 2 had anxiety plus depression, 4 had anxiety plus somatic disorder, 2 had depression plus somatic disorder, and 40 had all three symptoms. (3) correlation of radiation rectal injury grading with anxiety, depression, and somatic symptom disorder: as compared to patients in mild group and moderate group, those in severe group had higher severity of anxiety and somatic symptom disorder (Z=-2.143, P=0.032; Z=-2.045, P=0.041), while there was no statistically significant difference of depression between mild group and moderate group (Z=-1.176, P=0.240). Pearson correlation analysis revealed that radiation rectal injury symptom score was positively correlated with anxiety (r=0.300, P=0.013), depression (r=0.287, P=0.015) and somatic symptom disorder (r=0.344, P=0.003). Conclusions: The incidence of anxiety, depression, and somatic symptom disorder in patients with radiation rectal injury is extremely high. It is necessary to strengthen the diagnosis and treatment of somatic symptom disorder, so as to alleviate the symptoms of patients with pelvic perineum pain and improve the quality of life.
Aged ; Anxiety ; Cross-Sectional Studies ; Depression ; Female ; Humans ; Male ; Middle Aged ; Quality of Life ; Rectum ; Surveys and Questionnaires

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Objective: To investigate the effects of ticagrelor on cardiorespiratory fitness in patients with coronary heart disease after percutaneous coronary intervention (PCI). Methods: A total of 1 073 patients, who were diagnosed as coronary heart disease and underwent cardiopulmonary exercise testing (CPET) within 1 year after PCI, were enrolled from September 2017 to September 2019 in Peking University Third Hospital, including 309 patients in ticagrelor group and 764 patients in clopidogrel group. Clinical information, blood test results, echocardiographic parameters, cardiorespiratory fitness related parameters (including peak oxygen uptake (VO(2)), anaerobic threshold VO(2), peak oxygen pulse (VO(2)/HR) and carbon dioxide ventilation equivalent (VE/VCO(2)) slope), coronary lesions and intervention information were obtained. Cardiopulmonary fitness related indexes were compared between the two groups, and the correlation between ticagrelor use and cardiopulmonary fitness related indexes was analyzed by multivariate logistic regression. Patients who underwent CPET within 1 month after PCI were included in the subgroup analysis. Results: In ticagrelor group, the age was (60.3±10.3) years, and 253(81.9%) cases were male. The age of clopidogrel group was (60.6±10.0) years, and there were 608(79.6%) males. No significant differences were observed in peak VO(2), anaerobic threshold VO(2), and peak VO(2)/HR between the two groups (all P>0.05), but the VE/VCO(2) slope was significantly higher in the ticagrelor group than in the clopidogrel group (30.075 (27.207, 33.603) vs. 28.853 (25.970, 32.336), P<0.001). Logistic regression analysis suggested that the peak VO(2), anaerobic threshold VO(2) and peak VO(2)/HR were not significantly correlated with the ticagrelor use (all P>0.05), while the VE/VCO(2) slope was independently correlated with ticagrelor use (OR=1.098, 95%CI 1.032-1.168, P=0.003). Subgroup analysis of patients who underwent CPET within 1 month after PCI also indicated that no significant difference were observed in peak VO(2), anaerobic threshold VO(2), peak VO(2)/HR and VE/VCO(2) slope between the two groups (all P>0.05). Logistic regression analysis suggested that the peak VO(2), anaerobic threshold VO(2) and peak VO(2)/HR were not significantly correlated with ticagrelor use (all P>0.05), while the VE/VCO(2) slope was significantly correlated with ticagrelor use (OR=1.132, 95%CI 1.030-1.244, P=0.010). Conclusion: Among coronary heart disease patients after PCI, treatment with clopidogrel does not result in significant decrease in exercise endurance as compared with patients treated with ticagrelor.
Aged ; Cardiorespiratory Fitness ; Exercise Test ; Female ; Heart Failure ; Humans ; Male ; Middle Aged ; Oxygen Consumption ; Percutaneous Coronary Intervention ; Ticagrelor

Objective: This study was performed to evaluate the efficacy of metformin on liver fat content (LFC) in first episode schizophrenia patients with olanzapine-induced weight gain, and the relationship between the change of LFC and the other metabolic indices. Methods: In a double-blind study, the clinically stable inpatients with first-episode schizophrenia under olanzapine monotherapy who gained more than 7% of their baseline weight were randomly assigned to two groups; one with olanzapine plus metformin (1,000 mg/day) (metformin group) and the other with olanzapine plus placebo (placebo group) for 16 weeks. All patients continued to maintain the original olanzapine dosage. LFC was measured by magnetic resonance imaging at baseline and at the end of 16 weeks, respectively. At the same time, glucose and lipid metabolism, homeostasis model assessment of insulin resistance index (HOMA-IR) were measured respectively, analyzing the correlation between the change value of LFC and other indicators. Results: Over the 16-week study period, LFC value in metformin group decreased compared with baseline. LFC change across the 16-week treatment period was −2.91% for the metformin group and 0.59% for the placebo group, with a between-group difference of −3.5% (95% confidence interval, −6.08 to −0.93; p = 0.009). Compared to baseline, in the metformin group, triglyceride and HOMA-IR reduced significantly, while high density lipoprotein cholesterol increased significantly at weeks 16. There was positive correlation between LFC changes and triglycerides, HOMA-IR changes significantly. Conclusion Metformin can significantly attenuate LFC in schizophrenia patients with olanzapine-induced weight gain. It may be related to the improvement of the part of the glucolipid metabolic indices.