Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Comparison between 200 mg generic celecoxib hard capsules and Celebra®: bioequivalence study in healthy male and female subjects under fasting conditions after a single dose / Comparação entre celecoxibe genérico de 200 mg em cápsulas duras e Celebra®: estudo de bioequivalência em indivíduos saudáveis do sexo masculino e feminino, em jejum, após uma dose única

ABSTRACT BACKGROUND AND OBJECTIVES: The objective of this study was to assess the bioequivalence between two 200 mg celecoxib hard capsule formulations administered to healthy male and female participants under fasting conditions with the aim of providing an alternative pharmaceutical product to the reference drug, Celebra®. METHODS: A randomized, open label, single dose, 2x2 crossover trial was conducted with 60 adult healthy subjects under fasting conditions comparing single doses of two celecoxib hard capsules formulation. Pharmacokinetic parameters were calculated following the determination of drugs concentrations in human plasma using a validated liquid chromatography with a tandem mass spectrometer detector method (LC-MS/MS). RESULTS: Statistical analysis provided geometric mean of test/reference ratio, confidence intervals, intra-subject variation coefficient and power of the test to the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. Confidence intervals for the geometric mean (90% CI) of the test/reference drugs for celecoxib were 98.26 to 122.75% for Cmax, 100.27% to 110.78% for AUC0-t, and 96.87% to 110.29% for AUC0-∞. The power of the test found was 95.09% for Cmax, 100.00% for AUC0-t, and 99.99% for AUC0-∞. CONCLUSION: The formulations met the Brazilian standards for interchangeability, as the confidence intervals for Cmax and AUC0-t ratios are within the range of 80% to 125%, thus meeting the requirements of the legislation during market registration. The researched product was approved by the regulatory authorities and became a commercially competitive option to the reference product for the Brazilian population.

RESUMO JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi avaliar a bioequivalência entre duas formulações de cápsulas duras de celecoxibe de 200 mg administradas a participantes saudáveis do sexo masculino e feminino em condições de jejum com o objetivo de fornecer um produto farmacêutico alternativo ao fármaco de referência, Celebra®. MÉTODOS: Estudo randomizado, aberto, de dose única e cruzado 2x2. Foi conduzido com 60 indivíduos adultos saudáveis em condições de jejum, comparando doses únicas de duas formulações de cápsulas duras de celecoxibe. Os parâmetros farmacocinéticos foram calculados após a determinação das concentrações dos fármacos no plasma humano usando uma cromatografia líquida validada com um método detector de espectrômetro de massa em tandem (LC-MS/MS). RESULTADOS: A análise estatística forneceu a média geométrica da razão teste/referência, os intervalos de confiança, o coeficiente de variação intra-sujeito e o poder do teste para os parâmetros farmacocinéticos Cmáx, AUC0-t e AUC0-∞. Os intervalos de confiança para a média geométrica (IC 90%) dos fármacos teste/referência para o celecoxibe foram 98,26 a 122,75% para Cmáx, 100,27% a 110,78% para AUC0-t e 96,87% a 110,29% para AUC0-∞. O poder do teste encontrado foi de 95,09% para Cmáx, 100,00% para AUC0-t e 99,99% para AUC0-∞. CONCLUSÃO: As formulações atenderam aos padrões brasileiros de intercambialidade, pois os intervalos de confiança para as razões Cmáx e AUC0-t estão dentro da faixa de 80% a 125%, atendendo, assim, às exigências da legislação para o registro no mercado. O produto pesquisado foi aprovado pelas autoridades regulatórias e tornou-se uma opção comercialmente competitiva ao produto de referência para a população brasileira.

Determinants of time to viral clearance among SARS-CoV-2 infected individuals at Millennium COVID-19 care center in Ethiopia: A prospective observational study

Background: Understanding the COVID-19 disease course in terms of viral shedding is important to assist in providing a tailored isolation and treatment practice. Therefore, the current study aimed to estimate time to viral clearance and identify determinants among SARS-CoV-2 infected individuals admitted to Millennium COVID-19 Care Center in Ethiopia. Methods: A Prospective observational study was conducted among 360 randomly selected SARS-CoV-2 infected individuals who were on follow up from 2nd June to 5th July 2020. Kaplan Meier plots, median survival times, and Log-rank test were used to describe the data and compare survival distribution between groups. Association between time to viral clearance and determinants was assessed using the Cox proportional hazard survival model, where hazard ratio, P-value, and 95% CI for hazard ratio were used for testing significance Results: The Median time to viral clearance was 16 days. The log-rank test shows that having moderate and severe disease, one or more symptoms at presentation, and presenting with respiratory and constitutional symptoms seems to extend the time needed to achieve viral clearance. The Final Cox regression result shows that the rate of achieving viral clearance among symptomatic patients was 44% lower than patients who were asymptomatic (AHR=0.560, 95% CI=0.322-0.975, p-value=0.040). Conclusions: Presence of symptoms was found to be associated with delayed viral clearance implying that symptomatic patients are more likely to be infectious and therefore, attention should be paid to the practices regarding isolation and treatment of COVID-19 patients.

Estudo de expressão proteica de COX2 (PTGS2) em câncer colorretal metastático / A study on CDX2 and COX2 (PTGS2) protein expression in metastatic colorectal cancer

A perda de expressão do gene supressor de tumores CDX2 (fator de transcrição homeótico tipo caudal 2) está associada a resultados desfavoráveis em câncer colorretal em estágio inicial. No entanto, o seu valor prognóstico no contexto de outros biomarcadores prognósticos em câncer colorretal metastático (CCRm) é desconhecido. Superexpressão da proteína ciclooxigenase-2 (COX2) foi relatada em câncer colorretal avançado. No entanto, a relação entre CDX2 e COX2 em CCRm permanece indeterminada. Nosso objetivo foi avaliar a sua expressão em tumores de CCRm de uma coorte clinicamente caracterizada bem como o seu impacto na sobrevida global (SG) e na sobrevida livre de progressão (SLP) na primeira linha de tratamento.Dentre 720 pacientes consecutivos com CCRm, 346 apresentavam amostras tumorais apropriadas para montagem de microarranjos de tecidos e análises de imuno-histoquímica. Dados clínicos e de sobrevida foram avaliados retrospectivamente. A perda de expressão de CDX2 foi detectada em 27 (7,8%) amostras, enriquecidas em tumores pouco diferenciados (20%; p<0,01) e naqueles com a variante BRAF p.V600E (40%; p<0,01). A maioria dos tumores (93,4%) expressou COX2. Amostras negativas para COX2 foram mais comuns em CCRm pouco diferenciados. Em análises não ajustadas, a mediana da SG (p<0,001) e a mediana da SLP (p<0,05) foram inferiores para pacientes com tumores CDX2-negativos em comparação com tumores CDX2-positivos. Em conclusão, a perda de CDX2 mostrou uma associação significativa com CCRm pouco diferenciado e o alelo BRAF p.V600E, sendo um marcador prognóstico de piora da sobrevida global.

INTRODUCTION: Lack of expression of the tumor suppressor gene CDX2 associates with poor outcomes in early stage colorectal cancer. Yet its prognostic value in the context of other prognostic biomarkers in metastatic CCR (CCRm) is unknown. Overexpressed cyclooxygenase-2 (COX2), encoded by the prostaglandin-endoperoxide synthase 2 gene has been reported in advanced CCR. However, CDX2 and COX2 relationship in CCRm remains undetermined. We aimed to assess their expression in CCRm tumors from a clinically characterized cohort and their influence on overall survival (OS) and progression-free survival (PFS) in first line. METHODS: Demographic and clinical data from mCRC were retrospectively analyzed. Appropriate tumor samples were collected for tissue microarray and analyzed by immunohistochemistry. RESULTS: Three hundred and forty six mCRC were included. Loss of CDX2 expression was detected in 27 (7.8%) samples, enriched in poorly differentiated tumors (20%; p<0.01) and in those with the BRAF p.V600E variant (40%; p<0.01). Most tumors (93.4%) expressed COX2. COX2-negative samples were enriched in poorly differentiated CCRm. In unadjusted analyses, median OS (p<0.001) and median PFS (p<0.05) were inferior for patients with CDX2-negative versus CDX2-positive tumors. CONCLUSION:Loss of CDX2 was significantly associated with poorly differentiated CCRm and BRAF p.V600E allele and a prognostic marker of worse OS.

Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus Chemotherapy and Chemotherapy / 中国肺癌杂志

BACKGROUND@#The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC.@*METHODS@#46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC.@*RESULTS@#Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC.@*CONCLUSIONS@#Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.

Clinical characteristics and risk factors of renal function deterioration in children with renal dysplasia complicated with chronic kidney disease / 现代泌尿外科杂志

【Objective】 To explore the clinical characteristics and risk factors of renal function deterioration in children with renal dysplasia and chronic kidney disease (CKD), so as to provide a basis for the diagnosis, treatment, and management. 【Methods】 The clinical data of children with renal dysplasia complicated with CKD treated in the Children’s Hospital of Chongqing Medical University during 2012 and 2022 were retrospectively analyzed, including the gender, age of diagnosis, growth index, concomitant malformation and complications. According to the diagnostic criteria and staging standard of KDIGO2020 guidelines, patients with disease deteriorated to CKD stage 4-5 were enrolled into the regression group. Factors affecting the deterioration of renal function were determined with Cox regression analysis. 【Results】 A total of 122 children were involved, including 66 (54.1%) with CKD stag 4-5. There were more boys than girls. Bilateral and unilateral renal dysplasia occurred in 88 (72.13%) and 34 (27.87%) cases, respectively, and 64 (52.46%) cases were complicated with other urinary diseases. There were significant differences in weight, height and body mass index (BMI) among patients with CKD stage 1-5 (P<0.01). The age of onset of CKD <10 years, BMI lower than the 3rd percentile of the same sex and age, bilateral renal dysplasia, and one or more complications of congenital renal and urinary tract abnormalities (CAKUT) were the risk factors of deterioration of renal function (P<0.05). 【Conclusion】 Renal dysplasia complicated with CKD are more common in boys, with high incidence of bilateral renal dysplasia. Bilateral renal dysplasia, age of onset of CKD <10 years, BMI lower than 3% and complications are important influencing factors of renal dysplasia in children with CKD.

Development and preliminary evaluation of a fluorescence RPA assay for the rapid detection of Necator americanus / 中国热带医学

@#Abstract: Objective To establish a rapid detection assay based on fluorescence recombinase polymerase amplification (RPA) targeting Necator americanus eggs, and to evaluate its efficacy, providing technical support for rapid detection of Necator americanus in fecal samples. Methods The fluorescence RPA primers and probe were designed based on the cox1 gene of Necator americanus and then screened the optimal combination to develop the assay. The genomic DNA of Necator americanus eggs was diluted to 7 concentration gradients including 100 pg/µL, 10 pg/µL, 1 pg/µL, 100 fg/µL, 10 fg/µL, 1 fg/µL, 0.1 fg/µL, to determine the detection limit of the assay. The specificity of the assay was demonstrated by detected genomic DNA from Schistosoma japonicum, Ascaris lumbricoides, Clonorchis sinensis and Fasciola hepatica. A total of 44 fecal samples were collected and DNA extraction was performed, and the modified Kato-Katz method, semi-nest PCR method, and fluorescent RPA method were simultaneously used for detection to evaluate the sensitivity and specificity. Results The established fluorescence RPA assay can specifically amplify a fragment of 194 bp of the Necator americanus cox1 gene within 20 min, with a detection limit of 10 fg/µL. There was no cross-reactivity with Schistosoma japonicum, Ascaris lumbricoides, Clonorchis sinensis, Fasciola hepatica after specificity validation. In 44 fecal samples, 27 positive samples were detected by the fluorescence RPA assay, and 26 positive samples were detected by both the Kato-Katz and the semi-nested PCR. The fluorescence curve of sample number 1 was slightly higher than the negative control in the later stage of the reaction, but did not show a similar trend to the positive control, and was therefore judged to be a suspected negative sample. Compared with the Kato-Katz method and the semi-nest PCR method, The sensitivity of the fluorescent RPA method were 100.00% and the specificity were 94.44%, and the consistency of the detection results was good (Kappa=0.953>0.75). Conclusions The assay based on the fluorescence RPA is an efficient, sensitive and specific technique for detecting Necator americanus and it can be applied for surveillance and early warning of hookworm infection.

Influencing Factors of HIV/ AIDS Death Based on Bayesian Cox Proportional Hazard Regression Model / 中山大学学报(医学科学版)

ObjectiveTo understand the composition of related characteristics of HIV/AIDS cases in Lanzhou and analyze the influencing factors of AIDS-related deaths. MethodsThe information of HIV/AIDS cases reported in Lanzhou from 2011 to 2019 was collected， the method of survival was used analysis and Bayesian Cox Proportional Hazard Regression Model was constructed to analyze the related factors of death. ResultsA total of 2 312 HIV/AIDS patients were selected in this study， including 45 AIDS-related deaths. The results of multivariate regression showed that the older the patients were， the higher the risk of death was； the risk of death of AIDS patients at the time of diagnosis was 13.91 times higher than that of HIV-infected patients； Patients who received CD4 testing had a lower risk of death than those who did not； The risk of death was 0.22 times higher among those who received antiretroviral therapy than those who did not receive antiretroviral therapy. ConclusionsAge at diagnosis， course of disease， antiviral therapy were the influencing factors of AIDS-related death in HIV/AIDS patients in Lanzhou. Therefore， it is necessary to strengthen health education for AIDS-related groups， advocate early detection， early diagnosis， and early treatment， expand the coverage of AIDS testing and treatment， prolong the survival time of AIDS patients.

Effect of Tripterygium wilfordii Polyglycoside on Expression of NFAT2/COX-2 in Kidney Tissues of Rats with Diabetic Nephropathy / 中国实验方剂学杂志

ObjectiveTo explore the underlying mechanism of Tripterygium wilfordii polyglycoside tablets （TWPT） in the prevention and treatment of kidney injury in diabetic nephropathy （DN） through the nuclear factor of activated T-cells 2（NFAT2）/cyclooxygenase-2（COX-2） pathway. MethodForty-two male SD rats of SPF grade were selected and randomly divided into a normal group （n=8） and an experimental group （n=34） after one week of adaptive feeding. The rats in the normal group were fed conventionally. The DN model was established in rats of the experimental group by intraperitoneal injection of streptozotocin （STZ） following one week of feeding on a high-fat and high-glucose diet. After the death and failure cases during modeling were eliminated， the remaining 24 model rats were randomly divided into model group， valsartan （8.33 mg·kg-1·d-1） group， and TWPT （5 mg·kg-1·d-1） group. Rats in normal group and model group were given equal amounts of normal saline by gavage. After six weeks， body weight was measured and urine samples were collected. Blood samples were collected from the abdominal aorta， and then the rats were sacrificed for sampling. Biochemical indicators， such as serum blood urea nitrogen （BUN）， serum creatinine （SCr）， alanine aminotransferase （ALT）， blood lipid， blood glucose， and 24-hour urine total protein （24 h UTP）， were determined. Hematoxylin-eosin （HE） staining and Masson staining were used to observe the pathology of the kidney. Enzyme-linked immunosorbent assay （ELISA） was used to detect NFAT2 and COX-2 expression levels in the serum. Western blot and Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR）were adopted to detect NFAT2， COX-2 protein and mRNA expression in kidney tissues， respectively. ResultCompared with the normal group， the model group showed elevated 24 h UTP， BUN， SCr， CHO， TG， and FBG， increased serum NFAT2 and COX-2 production and expression （P<0.01）， and elevated protein and mRNA expression of NFAT2 and COX-2 in kidney tissues （P<0.01）. In addition， the pathology of the kidney showed enlarged glomeruli， mild proliferation of mesangial cells， and widened mesangial stroma. Compared with the model group， the TWPT group showed decreased 24 h UTP， BUN， SCr， CHO， TG， and FBG （P<0.05，P<0.01）， basically normal glomerular morphology， decreased expression of serum NFAT2 and COX-2 （P<0.01）， and down-regulated protein and mRNA expression of NFAT2 and COX-2 in kidney tissues （P<0.01）. ConclusionTWPT can alleviate 24 h UTP in DN model rats， protect renal function， and improve renal pathology， and its mechanism of action may be related to the down-regulation of NFAT2/COX-2 expression in the serum and kidney tissues.

Effects of moxibustion on serum levels of β-EP, SP and expression of IL-1β and COX-2 protein in brainstem in rats with migraine / 中国针灸

OBJECTIVE@#To observe the effects of moxibustion at "Baihui" (GV 20) and "Dazhui" (GV 14) at different time points on the serum level of β-endorphin (β-EP), substance P (SP) and expression of interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) protein in brainstem in rats with migraine, and to explore the effect and mechanism of moxibustion in preventing and treating migraine.@*METHODS@#Forty male SD rats were randomly divided into a blank group, a model group, a prevention+treatment (PT) group and a treatment group, 10 rats in each group. Except the blank group, the rats in the remaining groups were injected with nitroglycerin subcutaneously to prepare migraine model. The rats in the PT group were treated with moxibustion 7 days before modeling (once a day) and 30 min after modeling, while the rats in the treatment group were treated with moxibustion 30 min after modeling. The "Baihui" (GV 20) and "Dazhui" (GV 14) were taken for 30 minutes each time. The behavioral scores in each group were observed before and after modeling. After intervention, ELISA method was used to detect the serum level of β-EP and SP; the immunohistochemistry method was used to detect the number of positive cells of IL-1β in brainstem; the Western blot method was used to detect the expression of COX-2 protein in brainstem.@*RESULTS@#Compared with the blank group, the behavioral scores in the model group were increased 0-30 min, 60-90 min and 90-120 min after modeling (P<0.01); compared with the model group, in the treatment group and the PT group, the behavioral scores were decreased 60-90 min and 90-120 min after modeling (P<0.01). Compared with the blank group, in the model group, the serum level of β-EP was decreased (P<0.01), while the serum level of SP, the number of positive cells of IL-1β in brainstem and the expression of COX-2 protein were increased (P<0.01). Compared with the model group, in the PT group and and the treatment group, the serum level of β-EP was increased (P<0.01), while the serum level of SP, the number of positive cells of IL-1β and the expression of COX-2 protein in brainstem were decreased (P<0.01, P<0.05). Compared with the treatment group, in the PT group, the serum level of β-EP was increased and COX-2 protein expression was decreased (P<0.05).@*CONCLUSION@#Moxibustion could effectively relieve migraine. The mechanism may be related to reduce the serum level of SP, IL-1β and COX-2 protein expression in brainstem, and increase the serum level of β-EP, and the optimal effect is observed in the PT group.

Study on risk factors of recurrent Henoch-Schonlein purpura recurrence in children based on Cox regression analysis / 西安交通大学学报(医学版)

【Objective】 To explore the relevant risk factors of Henoch-Schonlein purpura (HSP) recurrence so as to provide some theoretical basis for early identification of children prone to recurrence. 【Methods】 The clinical data of 417 children with HSP hospitalized in Department of Pediatrics, The First Affiliated Hospital of Xi’an Jiaotong University, in the past five years were collected and followed up. They were divided into recurrent group and non-recurrent group. Cox regression analysis was used for univariate and multivariate analysis, and finally the independent risk factors for HSP recurrence were screened. 【Results】 A total of 417 children with initial onset of HSP were included in the study. During the follow-up period of 14 to 60 months, 78 cases recurred, and the recurrence rate was 18.7%. 94.9% of the children had relapse within 1 year. The results of univariate Cox regression analysis showed that age >7 years old at the time of onset, history of infection, history of strenuous exercise, duration of rashes more than 4 weeks, high level of neutrophil-to-lymphocyte ratio (NLR), and high level of platelet-to-lymphocyte ratio (PLR) were all risk factors for HSP recurrence (P7 years old at the time of onset, history of infection, history of strenuous exercise, duration of rashes for more than 4 weeks at the first onset, and high PLR level were independent risk factors for HSP recurrence (P 7 years at the time of onset, with a history of infection, vigorous exercise, rashes lasting more than 4 weeks, and high PLR level, nursing should be strengthened after discharge to avoid infection and vigorous exercise and increase the frequency of follow-up.

Expression of cuproptosis-related gene COX17 in breast cancer tissues and cells and its association with clinical features and patient prognosis / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探究铜死亡相关基因COX17在乳腺癌组织和细胞中的表达及其与肿瘤免疫细胞浸润、临床特征和患者预后的关系。方法：通过多种数据库数据分析COX17在人体正常组织和泛癌组织与细胞中的表达及其与患者预后的关系、COX17基因突变情况、COX17表达水平与肿瘤免疫微环境的相关性、COX17在浸润性乳腺癌中表达水平及其与患者临床病理特征的相关性、在乳腺癌细胞中COX17基因遗传突变及甲基化情况、COX17差异共表达基因的功能富集分析，构建COX17蛋白质相互作用网络及功能分析。采用免疫组化法检测COX17蛋白在国人乳腺癌组织中的表达以验证数据库分析结果。结果：COX17 mRNA广泛分布于全身组织中且在多数癌组织中呈高表达，COX17蛋白在乳腺癌等癌组织中呈高表达，COX17 mRNA表达水平明显影响乳腺癌等癌症患者的预后，COX17基因在多种癌组织中突变频率高且其主要突变类型为错义突变、扩增和深度缺失，COX17 mRNA表达水平与多种肿瘤的肿瘤纯度和多种免疫细胞浸润存在相关性，COX17蛋白水平与乳腺癌临床分期、病理分型、淋巴结转移、患者性别和年龄有关联。免疫组化法检测结果证实在国人乳腺癌组织中COX17蛋白也呈高表达，COX17基因在乳腺癌中遗传突变和修饰特征分别是截断突变和启动子区高度甲基化。COX17蛋白与ATOX1等多种蛋白表达相关且构成复杂的相互作用网络，COX17在乳腺癌中差异表达基因主要涉及氧化还原酶活性、蛋白翻译、氧化磷酸化及TNF信号通路等生物过程。结论：COX17在乳腺癌组织和细胞中呈高表达，且与癌组织的免疫细胞浸润和患者预后相关，COX17是临床治疗乳腺癌的潜在靶点。

Survival analysis on patients with occupational pneumoconiosis in Guangdong Province from 1980 to 2019 / 中国职业医学

Objective: To study the survival time and its risk factors of patients with occupational pneumoconiosis. Methods: A total of 11 011 newly diagnosed occupational pneumoconiosis patients in Guangdong Province from 1980 to 2019 were selected as study subjects. The life table method was used for survival analysis. The influencing factors of survival time of occupational pneumoconiosis patients were analyzed using the WilCoxon (Gehan) test and Cox proportional hazards regression model. Results: The median survival time of pneumoconiosis patients was 26.0 years. The median survival period of stage Ⅰpatients was 3.5 years longer than that of stage Ⅱ patients and 10.1 years longer than that of stage Ⅲ patients. The median survival time of patients with an initial diagnosis age under 40.0 years old was 34.8 years longer than that of patients with an initial diagnosis age over 60.0 years old. The median survival time of patients with dust exposure duration under 25.0 years old was 13.6 years longer than patients with dust exposure duration age over 45.0 years old. The results of the Cox proportional hazards regression model showed that the initial diagnosis stage, initial diagnosis age, dust exposure duration, and medical insurance were risk factors of the survival time of occupational pneumoconiosis patients (all P<0.01). The risk of reduced survival time for patients with stage Ⅱ and stage Ⅲ as the initial diagnosis stage was 1.15 and 2.04 times higher, respectively, compared with stage Ⅰ patients (both P<0.01). The risk of reduced survival time for patients without medical insurance was 60.22 times higher than those with medical insurance (P<0.01). Conclusion: The risk factors of the survival time of occupational pneumoconiosis patients in Guangdong Province are initial diagnosis stage, initial diagnosis age, the dust exposure age, and medical insurance. Earlier detection, earlier diagnosis, and improvement of medical insurance coverage for patients can effectively improve the survival time of occupational pneumoconiosis patients.

Development and validation of a prognostic model for patients with sepsis in intensive care unit / 中华危重病急救医学

Objective:To analyze the risk factors related to the prognosis of patients with sepsis in intensive care unit (ICU), construct a nomogram model, and verify its predictive efficacy.Methods:A retrospective cohort study was conducted using data from Medical Information Mart for Intensive Care-Ⅳ 0.4 [MIMIC-Ⅳ (version 2.0)]. The information of 6 500 patients with sepsis who meet the diagnostic criteria of Sepsis-3 were collected, including demography characteristics, complications, laboratory indicators within 24 hours after ICU admission, and final outcome. Using a simple random sampling method, the patients were divided into a training set and a validation set at a ratio of 7∶3. The restricted cubic spline (RCS) was used to explore whether there was a linear relationship between each variable and the prognosis, and the nonlinear variables were truncated into categorical variables. All variables were screened by LASSO regression and included in multivariate Cox regression analysis to analyze the death risk factors in ICU patients with sepsis, and construct a nomograph. The consistency index, calibration curve and receiver operator characteristic curve (ROC curve) were used to evaluate the prediction efficiency of nomogram model. The decision curve analysis (DCA) was used to validate the clinical value of the model and its impact on actual decision-making.Results:Among 6 500 patients with sepsis, 4 551 were in the training set and 1 949 were in the validation set. The 28-day, 90-day and 1-year mortality in the training set were 27.73% (1?262/4?551), 34.76% (1?582/4?551), and 42.98% (1?956/4?551), respectively, those in the validation set were 27.24% (531/1?949), 33.91% (661/1?949), and 42.23% (823/1?949), respectively. Both in training set and the validation set, compared with the final survival patients, the death patients were older, and had higher sequential organ failure assessment (SOFA) score and simplified acute physiology scoreⅡ (SAPSⅡ), more comorbidities, less urine output, and more use of vasoactive drugs, kidney replacement therapy, and mechanical ventilation. By RCS analysis, the variables with potential nonlinear correlation with the prognosis risk of septic patients were transformed into categorical variable. The variables screened by LASSO regression were enrolled in the multivariate Cox regression model. The results showed that age [hazard ratio ( HR) = 1.021, 95% confidence interval (95% CI) was 1.018-1.024], SOFA score ( HR = 1.020, 95% CI was 1.000-1.040), SAPSⅡ score > 44 ( HR = 1.480, 95% CI was 1.340-1.634), mean arterial pressure (MAP) ≤ 75 mmHg (1 mmHg ≈ 0.133 kPa; HR = 1.120, 95% CI was 1.026-1.222), respiratory rate (RR; HR = 1.044, 95% CI was 1.034-1.055), cerebrovascular disease ( HR = 1.620, 95% CI was 1.443-1.818), malignant tumor ( HR = 1.604, 95% CI was 1.447-1.778), severe liver disease ( HR = 1.330, 95% CI was 1.157-1.530), use of vasoactive drugs within 24 hours ( HR = 1.213, 95% CI was 1.101-1.336), arterial partial pressure of oxygen (PaO 2; HR = 0.999, 95% CI was 0.998-1.000), blood lactic acid (Lac; HR = 1.066, 95% CI was 1.053-1.079), blood urea nitrogen (BUN) > 8.9 mmol/L ( HR = 1.257, 95% CI was 1.144-1.381), total bilirubin (TBil; HR = 1.023, 95% CI was 1.015-1.031), and prothrombin time (PT) > 14.5 s ( HR = 1.232, 95% CI was 1.127-1.347) were associated with the death of ICU patients with sepsis (all P < 0.05). Based on the above factors, a nomogram model was constructed, and the model validation results showed that the consistency index was 0.730. The calibration curve showed a good consistency between the predicted results of the nomogram model and observed results in the training and validation sets. ROC curve analysis showed that the area under the ROC curve (AUC) predicted by the nomogram model in the training set and the validation set for 28-day, 90-day and 1-year death risk was 0.771 (95% CI was 0.756-0.786) and 0.761 (95% CI was 0.738-0.784), 0.777 (95% CI was 0.763-0.791) and 0.765 (95% CI was 0.744-0.787), 0.677 (95% CI was 0.648-0.707) and 0.685 (95% CI was 0.641-0.728), respectively. DCA analysis showed that the nomogram model had significant net benefits in predicting 28-day, 90-day, and 1-year death risk, verifying the clinical value of the model and its good impact on actual decision-making. Conclusions:The death risk factors related to ICU patients with sepsis include age, SOFA score, SAPSⅡ score > 44, MAP ≤ 75 mmHg, RR, cerebrovascular disease, malignant tumors, severe liver disease, use of vasoactive drugs within 24 hours, PaO 2, Lac, BUN, TBil, PT > 14.5 s. The nomogram model constructed based on this can predict the death risk of ICU patients with sepsis.

Efficacy of machine learning models versus Cox regression model for predicting prognosis of esophagogastric junction adenocarcinoma / 南方医科大学学报

OBJECTIVE@#To compare the performance of machine learning models and traditional Cox regression model in predicting postoperative outcomes of patients with esophagogastric junction adenocarcinoma (AEG).@*METHODS@#This study was conducted among 203 AEG patients with complete clinical and follow-up data, who were treated in our hospital between September, 2015 and October, 2020. The clinicopathological data of the patients were processed for analysis using R language package and divided into training and validation datasets at the ratio of 3:1. The Cox proportional hazards regression model and 4 machine learning models were constructed for analyzing the datasets. ROC curves, calibration curves and clinical decision curves (DCA) were plotted. Internal validation of the machine learning models was performed to assess their predictive efficacy. The predictive performance of each model was evaluated by calculating the area under the curve (AUC), and the model fitting was assessed using the calibration curve.@*RESULTS@#For predicting 3-year survival based on the validation dataset, the AUC was 0.870 for Cox proportional hazard regression model, 0.901 for eXtreme Gradient Boosting (XGBoost), 0.791 for random forest, 0.832 for support vector machine, and 0.725 for multilayer perceptron; For predicting 5-year survival, the AUCs of these models were 0.915, 0.916, 0.758, 0.905, and 0.737, respectively. For internal validation, the AUCs of the 4 machine learning models decreased in the order of XGBoost (0.818), random forest (0.758), support vector machine (0.0.804), and multilayer perceptron (0.745).@*CONCLUSION@#The machine learning models show better predictive efficacy for survival outcomes of patients with AEG than Cox proportional hazard regression model, especially when proportional odds assumption or linear regression models are not applicable. XGBoost models have better performance than the other machine learning models, and the multi-layer perception model may have poor fitting results for a limited data volume.

Predictive value of stress-induced hyperglycemia on 28 d risk of all-cause death in intensive care patients / 北京大学学报(医学版)

OBJECTIVE@#To investigate the relationship between stress glucose elevation and the risk of 28 d all-cause mortality in intensive care unit (ICU) patients, and to compare the predictive efficacy of different stress glucose elevation indicators.@*METHODS@#ICU patients who met the inclusion and exclusion criteria in the Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) database were used as the study subjects, and the stress glucose elevation indicators were divided into Q1 (0-25%), Q2 (>25%- 75%), and Q3 (>75%-100%) groups, with whether death occurred in the ICU and the duration of treatment in the ICU as outcome variables, and demographic characteristics, laboratory indicators, and comorbidities as covariates, Cox regression and restricted cubic splines were used to explore the association between stress glucose elevation and the risk of 28 d all-cause death in ICU patients; and subject work characteristics [receiver operating characteristic (ROC) and the area under curve (AUC)] were used to evaluate the predictive efficacy of different stress glucose elevation indicators, The stress hyperglycemia indexes included: stress hyperglycemia ratio (SHR1, SHR2), glucose gap (GG); and the stress hyperglycemia index was further incorporated into the Oxford acute severity of illness score (OASIS) to investigate the predictive efficacy of the improved scores: the AUC was used to assess the score discrimination, and the larger the AUC indicated, the better score discrimination. The Brier score was used to evaluate the calibration of the score, and a smaller Brier score indicated a better calibration of the score.@*RESULTS@#A total of 5 249 ICU patients were included, of whom 7.56% occurred in ICU death. Cox regression analysis after adjusting for confounders showed that the HR (95%CI) for 28 d all-cause mortality in the ICU patients was 1.545 (1.077-2.217), 1.602 (1.142-2.249) and 1.442 (1.001-2.061) for the highest group Q3 compared with the lowest group Q1 for SHR1, SHR2 and GG, respectively, and The risk of death in the ICU patients increased progressively with increasing indicators of stressful blood glucose elevation (Ptrend < 0.05). Restricted cubic spline analysis showed a linear relationship between SHR and the 28 d all-cause mortality risk (P>0.05). the AUC of SHR2 and GG was significantly higher than that of SHR1: AUCSHR2=0.691 (95%CI: 0.661-0.720), AUCGG=0.685 (95%CI: 0.655-0.714), and AUCSHR1=0.680 (95%CI: 0.650-0.709), P < 0.05. The inclusion of SHR2 in the OASIS scores significantly improved the discrimination and calibration of the scores: AUCOASIS=0.820 (95%CI: 0.791-0.848), AUCOASIS+SHR2=0.832 (95%CI: 0.804-0.859), P < 0.05; Brier scoreOASIS=0.071, Brier scoreOASIS+SHR2=0.069.@*CONCLUSION@#Stressful glucose elevation is strongly associated with 28 d all-cause mortality risk in ICU patients and may inform clinical management and decision making in intensive care patients.

Mechanism of Flavonoids from Mulberry Leaves on Insulin Resistance and Inflammatory Response in Diabetic Mice / 中国实验方剂学杂志

ObjectiveTo observe the glucose-lowering， insulin resistance-improving， and anti-inflammatory effects of flavonoids from mulberry leaves （FML） and explore their underlying mechanism. MethodMale db/db mice aged 6-7 weeks were randomly divided into a model group， a high-dose FML group （1.00 g·kg·d-1）， and a low-dose FML group （0.50 g·kg-1·d-1）. C57BL mice of the same age were assigned to the normal group. After six weeks of intervention， fasting blood glucose （FBG）， serum fasting insulin levels （Fins）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， free fatty acid （FFA）， blood creatinine （SCr）， blood urea nitrogen （BUN）， and aspartate aminotransferase （AST） levels were measured， and the homeostasis model assessment of insulin resistance （HOMA-IR） was calculated. Superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px）， and catalase activities in the liver were measured. Morphological changes in the liver were assessed by hematoxylin-eosin （HE） staining. The protein expression of cyclooxygenase-2 （COX-2）， inducible nitric oxide synthase （iNOS）， and nuclear factor-κB （NF-κB） in the liver was detected by Western blot. ResultCompared with the model group， the high-dose and low-dose FML groups showed significant reductions in FBG， Fins， HOMA-IR， IL-6， TNF-α， and FFA levels （P<0.05， P<0.01）， and increased levels of SOD， GSH-Px， and catalase in the liver （P<0.05， P<0.01）. HE staining of the liver in the FML groups showed improved arrangement of hepatocytes， reduced inflammatory cell infiltration， and alleviated cellular steatosis compared with the model group. The protein expression of COX-2， iNOS， and NF-κB in the liver significantly decreased in the FML groups as compared with that in the model group （P<0.05， P<0.01）. ConclusionFML have glucose-lowering and insulin resistance-improving effect， which may be attributed to their regulation of the NF-κB pathway in the liver of diabetic mice， leading to the suppression of the release of COX-2， iNOS， and inflammatory cytokines， thereby improving the inflammatory state.

Epidemiological characteristics of Cox A6 infected with hand-foot-mouth disease in children aged 1-12 years in Enshi / 公共卫生与预防医学

Objective To investigate the incidence and risk factors of severe cases of Cox A6 infected with HAND-foot-mouth disease in 1-12 years old children in Enshi city, and to provide reference for prevention and treatment of hand-foot-mouth disease. Methods From January to September 2021, hospitalized children aged 1-12 years with HFMD in Enshi city were collected. The samples of anal swabs and throat swabs were tested for Coxsackie virus A6 (Cox A6) nucleic acid, and the distribution of Cox A6 patients infected with HFMD and the proportion of severe cases in children aged 1-12 years were analyzed. Logistic regression was used to analyze the risk factors of severe cases. Results From January to September 2021, a total of 343 HFMD cases aged 1 to 12 years were reported in Enshi, among which 241 cases (70.26%) were infected with CoxA6. No death cases were reported during the period. The 241 cases of Cox A6 infected with HFMD were distributed from January to September. 129 males (53.53%) and 112 females (46.47%); 208 cases (44.40%) were mainly from 1 to 3 years old, followed by 66 cases (28.39%) from 4 to 6 years old, 45 cases (18.67%) from 7 to 9 years old, and 23 cases (9.54%) from 10 to 12 years old. Cox A6 was mainly infected with HFMD in 145 cases (60.17%) in rural areas and 96 cases (39.83%) in urban areas. 10 cases (4.15%) of Cox A6 infected HFMD were severe cases; There were significant differences in age, fever temperature, fasting blood glucose and fever time between the severe case group and the normal case group (P<0.05). Logistic multivariate regression analysis showed that fever temperature (OR=1.559, P<0.05), fasting blood glucose (OR=2.472, P<0.05) and fever time (OR=2.932, P<0.05) were independent risk factors for the occurrence of severe cases of Cox A6 infected with HFMWD in Enshi. Conclusion The incidence of Cox A6 infected with HFMD in Enshi is mainly concentrated in boys under 3 years old. Clinical treatment of HFMD children should focus on children with high fever temperature, fasting blood glucose and long fever time.

Comparison of prediction ability of two extended Cox models in nonlinear survival data analysis / 南方医科大学学报

OBJECTIVE@#To compare the predictive ability of two extended Cox models in nonlinear survival data analysis.@*METHODS@#Through Monte Carlo simulation and empirical study and with the conventional Cox Proportional Hazards model and Random Survival Forests as the reference models, we compared restricted cubic spline Cox model (Cox_RCS) and DeepSurv neural network Cox model (Cox_DNN) for their prediction ability in nonlinear survival data analysis. Concordance index was used to evaluate the differentiation of the prediction results (a larger concordance index indicates a better prediction ability of the model). Integrated Brier Score was used to evaluate the calibration degree of the prediction (a smaller index indicates a better prediction ability).@*RESULTS@#For data that met requirement of the proportion risk, the Cox_RCS model had the best prediction ability regardless of the sample size or deletion rate. For data that failed to meet the proportion risk, the prediction ability of Cox_DNN was optimal for a large sample size (≥500) with a low deletion (< 40%); the prediction ability of Cox_RCS was superior to those of other models in all other scenarios. For example data, the Cox_RCS model showed the best performance.@*CONCLUSION@#In analysis of nonlinear low maintenance data, Cox_RCS and Cox_DNN have their respective advantages and disadvantages in prediction. The conventional survival analysis methods are not inferior to machine learning or deep learning methods under certain conditions.