MiR-878 Aggravates Hypoxia/Reoxygenation Injury in H9c2 Cardiomyocytes by Inducing Pim1-mediated Mitochondrial Fission / 生物化学与生物物理进展

ObjectiveAcute myocardial infarction (AMI) is a highly prevalent and deadly disease globally, with its incidence continuing to rise in recent years. Timely reperfusion therapy is crucial for improving the prognosis of AMI patients. However, myocardial reperfusion can lead to irreversible myocardial ischemia/reperfusion (MI/R) injury, which is associated with adverse cardiovascular outcomes following AMI. Studies have shown that microRNAs (miRNAs) are abnormally expressed during MI/R injury and play an important role in the fate of cardiomyocytes. Effective preventive and therapeutic strategies against MI/R injury remain lacking in clinical practice, necessitating elucidation of the molecular mechanisms underlying MI/R onset and progression. This study investigated the role of microRNA-878 (miR-878) in the regulation of mitochondria-mediated apoptosis in MI/R injury. MethodsThe H9c2 cells were flushed with a gas mixture containing 1% O2, 5% CO2 and 94% N2 for 3 h. Then the cells were incubated in complete culture medium under 5% CO2 and 95% air for 6 h to mimic in vivo hypoxia/reoxygenation (H/R) injury. Cell viability were detected by CCK-8 assay. The concentrations of lactate dehydrogenase (LDH) were then measured.The level of apoptosis was analyzed by flow cytometry. The morphology of mitochondria was analyzed by immunofluorescence and laser confocal microscopy. The levels of mitochondrial reactive oxygen species (mtROS) were detected by immunofluorescence. Dual luciferase reporter gene assay was used to study the binding site of miR-878 and Pim1. RNA immunoprecipitation (RIP) assay was used to verify the binding relationship between miR-878 and Pim1. The gene expression levels were detected by real-time fluorescent quantitative PCR (RT-qPCR) and Western blot. ResultsThe study found that compared with the control group, the expression of miR-878 in H/R-treated H9c2 cells was significantly increased ((1.00±0.25) vs (9.70±2.63), P<0.01). In H/R-induced cells, transfection of miR-878 inhibitor significantly increased cell viability ((46.67±3.00) vs (74.62±4.08), P<0.000 1), and decreased LDH release ((358.58±41.71) vs (179.09±15.59), P<0.000 1) and cell apoptosis rate ((43.41±0.72) vs (27.42±4.48), P<0.01). At the same time, downregulation of miR-878 expression significantly inhibited DRP1-mediated mitochondrial overdivision and mtROS production ((6.60±0.57) vs (4.32±0.91), P<0.000 1). The mechanism study showed that miR-878 could target and bind Pim1 and inhibit the expression level of Pim1 ((1.00±0.13) vs (0.38±0.03), P<0.01). Rescue experiments confirmed that down-regulation of Pim1 expression significantly reversed the anti-injury effect of miR-878 inhibitor in H9c2 cells (P<0.01), promoted mitochondrial overdivision and mtROS production ((1.00±0.12) vs (2.41±0.12), P<0.01), and decreased the expression level of p-DRP1 ((1.00±0.15) vs (0.59±0.06), P<0.05). ConclusionThe present study demonstrates that miR-878 expression is upregulated in H9c2 cardiomyocytes subjected to H/R injury. Inhibition of miR-878 expression alleviates H/R-induced cardiomyocyte damage. Notably, downregulation of miR-878 significantly inhibits DRP1-mediated mitochondrial fission and mitigates mtROS production. Mechanistically, miR-878 targets and binds to the 3'-UTR of the Pim1 gene, thereby suppressing Pim1 protein expression. Collectively, these findings suggest that under H/R conditions, miR-878 promotes excessive mitochondrial fragmentation through DRP1 activation by targeting Pim1, ultimately contributing to cardiomyocyte injury. Modulation of the miR-878/Pim1 axis may represent a potential therapeutic strategy for mitigating MI/R-induced cardiac damage.

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

Mutation of proviral integration site for Moloney murine leukemia virus 1 in diffuse large B-cell lymphoma and its clinical significance / 白血病·淋巴瘤

Objective:To investigate the mutation of proviral integration site for Moloney murine leukemia virus 1 (PIM1) in diffuse large B-cell lymphoma (DLBCL) and its clinical significance.Methods:Paraffin-embedded tissues of 38 DLBCL patients surgically resected at Shiyan Taihe Hospital from January 2016 to March 2022 were collected. The mutation of PIM1 gene was detected by polymerase chain reaction (PCR)-Sanger sequencing. The DLBCL-related DUKE, DFCI and TCGA datasets in the cBioPortal database were screened to collect information on PIM1 gene mutation and expression and clinical prognosis. Patients were divided into PIM1 mutation-positive group and PIM1 mutation-negative group, and the differences in clinicopathological characteristics, tumor mutational burden (TMB), microsatellite instability (MSI) levels and overall survival (OS) between the two groups were compared. Kaplan-Meier method was used for survival analysis, and univariate and multivariate survival analyses were performed using Cox proportional hazards model.Results:The PIM1 mutation rates of DLBCL patients in DUKE, DFCI, TCGA datasets and Shiyan Taihe Hosipital were 14.3% (96/673), 26.3% (26/99), 19.5%(8/41) and 28.9% (11/38), respectively, in which mutation site and mutation form were more commonly found in exon 4 and missense mutations. There were statistical differences in the PIM1 mutation rate among DLBCL patients with different age (DUKE dataset) and cell of origin (COO) classification (DFCI dataset) ( χ2 values were 8.22 and 4.40, both P<0.05). Compared with PIM1 mutation-negative group, the PIM1 mutation-positive group had a higher TMB in DUKE, DFCI and TCGA datasets (all P<0.05). In DUKE and DFCI datasets, the OS of PIM1 mutation-positive group was worse than that of PIM1 mutation-negative group (both P<0.05), and multivariate Cox regression analysis showed that PIM1 gene mutation-positive was an adverse prognostic factor of OS (DUKE dataset: HR = 1.661, 95% CI 1.151-2.396, P = 0.007; DFCI dataset: HR = 2.074, 95% CI 1.031-4.172, P =0.041). Conclusions:PIM1 gene mutation may be related to the poor prognosis of DLBCL patients.

Shear stress regulateing the phosphorylation of endothelial nitric oxide synthase Ser633 and Ser1177 in human umbilical vein endothelial cells through Pim1 / Akt pathway / 解剖学报

[Abstract] Objective To explore the effect of different modes of blood flow shear stress on the Pim1 expression in human umbilical vein endothelial cells (HUVECs) and the regulation of phosphorylation at Ser1177 and Ser633 of endothelial nitric oxide synthase (eNOS). Methods HUVECs were isolated from fresh human umbilical cord. The parallel plate flow chamber system was used to load 15 dyn/ cm

Potential inappropriate medication and its influencing factors among elderly hypertensive patients in community general practice clinic / 中华全科医师杂志

Objective:To investigate the status quo of potentially inappropriate medication (PIM) among elderly hypertensive patients in community general practice clinic and related influencing factors.Methods:A total of 767 prescriptions for elderly hypertensive patients in a community health service center in Beijing from October 2020 to August 2021 were reviewed. The prevalence of PIM was assessed based on the criteria of potentially inappropriate medications for older adults in China(2017). Logistic regression analysis was employed to analyze the influencing factors for PIM. Results:The survey showed that 198 elderly patients had PIM with 244 person-doses. The top three drugs with high rate of PIM were benzodiazepine-estazolam (64 person-doses), clopidogrel (53 person-doses) and insulin (35 person-doses). Univariate analysis showed that PIM was significantly associated with types of medication;and underlying diseases hypertension with hyperlipidemia, coronary heart disease, type 2 diabetes, osteoarthritis, upper respiratory tract infection and insomnia (χ 2=82.58, 13.65, 17.74, 7.52, 10.34, 68.19,respectively,all P<0.05). Multivariate logistic regression analysis showed that the types of medication, hypertension complicated with upper respiratory tract infection, and insomnia were independent influencing factors for PIM ( OR=1.55, 2.47, 9.05; P<0.05). Conclusion:The study shows that PIM is more common in elderly hypertensive patients in community general practice clinics,which is associated with types of medication, hypertension complicated with upper respiratory tract infection and insomnia. It is suggested that general practitioner working in community clinics should be aware of PIM, minimize the number of prescription drugs, and choose new drugs or non-drug treatments to reduce the occurrence of PIM.

Desempenho do PRISM III e do PIM 2 em unidade de terapia intensiva pediátrica oncológica / Performance of PRISM III and PIM 2 scores in a cancer pediatric intensive care unit

RESUMO Objetivo: Avaliar o desempenho do Pediatric Risk of Mortality (PRISM) III e do Pediatric Index of Mortality (PIM) 2 em unidade de terapia intensiva pediátrica. Métodos: Estudo de coorte retrospectivo. Os dados retrospectivos foram coletados dos prontuários de todos os pacientes admitidos na unidade de terapia intensiva pediátrica de um hospital infantil oncológico, entre janeiro de 2017 a junho de 2018. Resultados: A média do PRISM III foi de 15 e do PIM 2 de 24%. Dos 338 pacientes estudados, 62 (18,34%) morreram. A mortalidade estimada pelo PRISM III foi de 79,52 (23,52%) e pelo PIM 2 de 80,19 (23,72%) pacientes, correspondendo a taxa padronizada de mortalidade (intervalo de confiança de 95%) de 0,78 para o PRISM II e 0,77 para o PIM 2. O teste de ajuste de Hosmer-Lemeshow obteve qui-quadrado de 11,56, 8df, com p = 0,975, para PRISM III, e qui-quadrado de 0,48, 8df, p = 0,999, para o PIM 2. Foi obtida área sob a curva Característica de Operação do Receptor de 0,71 para o PRISM III e 0,76 para o PIM 2. Conclusão: Os dois escores superestimaram a mortalidade e demonstraram poder regular de discriminação entre sobreviventes e não sobreviventes. Devem ser desenvolvidos modelos para quantificar a gravidade de pacientes pediátricos com câncer em unidade de terapia intensiva pediátrica e predizer o risco de mortalidade que contemplem suas peculiaridades.

ABSTRACT Objective: To assess the performance of Pediatric Risk of Mortality (PRISM) III and Pediatric Index of Mortality (PIM) 2 scores in the pediatric intensive care unit. Methods: A retrospective cohort study. Data were retrospectively collected from medical records of all patients admitted to the pediatric intensive care unit of a cancer hospital from January 2017 to June 2018. Results: The mean PRISM III score was 15, and PIM 2, 24%. From the 338 studied patients, 62 (18.34%) died. The PRISM III estimated mortality was 79.52 patients (23.52%) and for PIM 2 80.19 patients (23.72%), corresponding to a standardized mortality ratio (95% confidence interval: 0.78 for PRISM II and 0.77 for PIM 2). The Hosmer-Lemeshow chi-square test was 11.56, 8df, 0.975 for PRISM II and 0.48, 8df, p = 0.999 for PIM 2. The area under the Receiver Operating Characteristic curve was 0.71 for PRISM III and 0.76 for PIM 2. Conclusion: Both scores overestimated mortality and have shown a regular ability to discriminate between survivors and non-survivors. Models should be developed to quantify the severity of cancer pediatric patients in Pediatric Intensive Care Units and to predict the mortality risk accounting for their peculiarities.

Evaluation of Potentially Inappropriate Medication in Elderly Hospitalized Patients in Our Hospital Based on 2019 Beers Criteria / 中国药学杂志

OBJECTIVE: To investigate and analyze the potential inappropriate medication(PIM) in elderly hospitalized patients in our hospital, explore the related risk factors, and analyze the use of PIM involved drugs in different departments, so as to provide reference for the formulation of medication manuals for the elderies in different departments and for further standardizing the use of drugs in elderly patients. METHODS: The medical advice for elder patients(≥65 years old)hospitalised from January to October 2017 in our hospital was collected. Beers criteria of American Geriatrics Association 2019 was used as the reference to investigate and analyze PIM. And the risk factors of PIM were analyzed by logistic regression. RESULTS: The average age of 12 756 elderly hospitalized patients was (74.13±6.88) years and the average number of diseases per patient was (3.22±2.09). For each patient, (4.79±3.76) kinds of medicines were used. According to the 2019 Beers criteria, the incidence of PIM was 20.00%. Among them, the central nervous system medications(6.41%, 818/12 756) (estazolam tablets, alprazolam tablets) were the most frequently used. Data of PIM occurrence in different departments showed that the PIM incidence was higher in rheumatology, geriatrics, rehabilitation, anesthesia surgery and oncology departments. In addition, logistic regression analysis showed that gender, age, the number of combined medications and diseases, and length of stay were all potential risk factors for PIM. CONCLUSION: The incidence of PIM in elderly hospitalized patients in our hospital is high. The rational drug use in elderly patients needs to be improved.

Synergistic role of JAK/STAT5 and PI3K/AKT signaling pathways in regulating eIF4B in acute leukemia / 生物工程学报

Human acute leukemia (AL) is a clonal malignancy with abnormal hematopoietic stem cells. Clinically, AL is very difficult to cure due to its sudden onset and short course of disease progression. Previous studies have shown that eukaryotic initiation factor 4B (eIF4B) plays a critical role in the development of chronic leukemia. However, the involvement of eIF4B in human acute leukemia is still largely unknown. Therefore, we studied eIF4B function and its regulatory mechanism in human acute leukemia. We found that phosphorylation levels of eIF4B in acute leukemia cells were significantly reduced in response to treatment with either LY294002 (PI3K inhibitor), AKTi (AKT inhibitor) or SMI-4A (Pim inhibitor). Co-treatment with inhibitors targeting JAK/STAT5/Pim and PI3K/AKT/mTOR signaling dramatically promoted apoptosis of acute leukemia cells by downregulating eIF4B phosphorylation. Furthermore, in vitro and in vivo functional experiments showed that eIF4B played an important anti-apoptosis role in the acute leukemia cells by regulating the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL. In contrast, silencing eIF4B inhibited the growth of acute leukemia cells as engrafted tumors in nude mice. Taken together, our results indicate the synergistic role of JAK/STAT5/Pim and PI3K/AKT/mTOR signaling pathways in regulating eIF4B phosphorylation in acute leukemia, and highlight eIF4B as a candidate therapeutic target for treatment of acute leukemia.

Comparison of Beers criteria and EU(7) potentially inappropriate medications list for the potentially inappropriate medications in Indian elderly inpatients

Background: Use of inappropriate medication is an important problem in present geriatric clinical practice. No specific potentially inappropriate medications (PIM) tools are available considering the availability of drugs in India. Aim and objective were to assess prevalence and pattern of potentially inappropriate medication (PIM) use in elderly inpatients by updated Beers criteria 2015 and EU(7) PIM list 2015.Methods: This cross-sectional study was carried out on medical records of elderly patients (?65 yrs) admitted in the internal medicine wards and intensive care units (ICU) over a period of 6 weeks. The medications were evaluated for the PIM use as per Beers criteria and EU(7) PIM list.Results: A total of 225 patients (mean age- 71.48 yrs) were admitted in internal medicine wards and ICU during study period. Total 184 PIM belonged to 33 different medications were used during study period. The prevalence of PIM in internal medicine wards and ICUs were 51.96% and 57.14%, respectively. The prevalence of PIM was significantly higher with the EU(7) PIM list than Beers criteria (49.77% vs. 21.77%) [p<0.0001]. The commonly prescribed PIM were dextromethorphan (13.33%), ranitidine (11.11%) and glipizide (10.22%).Conclusions: Elderly patients frequently receive PIM. EU(7) PIM list identifies more PIM among elderly inpatients than Beers criteria.

Clinical profile and outcome of shock in mechanically ventilated patients in pediatric intensive care unit of tertiary care centre

Background: The clinical syndrome of shock, a clinical state characterized by inadequate tissue perfusion, is one of the most dramatic, dynamic and life-threatening problems faced by the physician in the critical care setting.Methods: Retrospective observational study of all critically ill children between 1month-12years who were admitted and mechanically ventilated in our 8-bedded PICU between January 2015 to June 2016; and had clinical evidence of shock. PIM3 (Paediatric Index of Mortality 3) was calculated. Authors noted morbidity and mortality pattern in all types of shock including outcome in Paediatric ICU. The data collected were compiled and tabulated.Results: The frequency of shock in authors’ Paediatric intensive care unit was 8.6% (n=780). However, among mechanically ventilated patients it was present in 65.5% patients. Septic shock was the most commonly encountered shock (n=48, 61.5%). Mortality was highest in cardiogenic shock (n=12, 80%) and obstructive shock (n=4, 80%). Survival was best in Hypovolemic shock. Authors found significant correlation between LOS MV and mortality (p=0.018). Type of shock had no correlation with PIM3 score (p=0.374) and mortality (p=0.884). Blood culture yield was positive in 26.9% patients with Klebsiella pneumoniae, Pseudomonas aeruginosa and MRSA being most common organisms isolated.Conclusions: Shock is a major cause of morbidity and mortality in children especially below 5yrs of age. Septic shock was the commonest form of shock in children. Severe pneumonia was the commonest illness causing septic shock. Mortality was associated with longer length of stay on mechanical ventilation. Larger prospective multicentric study in developing countries is desirable.

Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells. MATERIALS AND METHODS: The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis. RESULTS: AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. CONCLUSION: Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.

Recent advances of PIM kinase and its small-molecule inhibitors / 药学学报

Provirus Integration in Maloney murine leukemia virus (PIM) represents a novel class of unique Ser/Thr kinase, which has been identified to be over-expressed in multiple hematological malignancies and some solid tumors, and the expression quantity correlates with malignant grade and poor prognosis in patients with cancer. PIM kinase plays important roles in regulation of cell proliferation and differentiation through the phosphorylation of its protein substrates, and it has become the emerging target for cancer treatment. A large number of highly active PIM kinase inhibitors have been reported by domestic and foreign research institutions, and the research progress will be summarized according to affiliations in this review.

Expressions of p53, p63 and PIM1 proteins in nodal or extranodal diffuse large B-cell lymphoma and their prognostic significance / 肿瘤

Objective: To investigate the correlation between the expression of p53, p63 or PIM1 protein and the survival of patients with nodal or extranodal diffuse large B-cell lymphoma (DLBCL). Methods: Immunohistochemical staining was applied to examine the expressions of p53, p63 and PIM1 proteins in nodal or extranodal DLBCL. The differences in the expressions of p53, p63 and PIM1 proteins between nodal and extranodal DLBCL were analyzed by χ2 test. Kaplan-Meier survival curve and COX proportional hazard model were used to analyze the relationship between the clinicopathological factors (including p53, p63 and PIM1 expressions) and the prognosis of patients with nodal or extranodal DLBCL. Results: Among 212 DLBCL cases, there were 101 nodal cases and 111 extranodal cases (including 55 cases of gastrointestinal DLBCL and 56 cases of non-gastrointestinal DLBCL). The expression rates of p53, p63 and PIM1 proteins in all cases were 19.0%, 25.2% and 54.7%, respectively. Among them, p53 was expressed more frequently in extranodal gastrointestinal cases (P 0.05). Much more p53-positive cases were observed with international prognostic index (IPI) ≥ 3 (P 0.05). Survival analysis showed that the expression of p53 or p63 protein was a significant inferior prognostic factor for overall survival (OS) and progression-free survival (PFS) in nodal patients or extranodal non-gastrointestinal DLBCL patients, respectively (both P < 0.05), while PIM1 expression was an inferior prognostic factor for PFS in extranodal gastrointestinal cases (P < 0.05). Conclusion: The molecular mechanisms of DLBCL pathogenesis may be different between different locations of DLBCL, which is worth further exploration.

Comparación de una escala, un indice y un biomarcador como predictores de mortalidad en niños con choque séptico que ingresan a la unidad de terapia intensiva del hospital Dr. José Renán Esquivel. Agosto 2015- marzo 2016 / Comparison of a scale, an index and a biomarker as predictors of mortality in children with septic shock admitted to the intensive care unit of the Dr. José Renán Esquivel hospital. August 2015- March 2016

Resumen El choque séptico es una entidad que en la población pediátrica se ve asociado a altas tasas de morbilidad y mortalidad. En las unidades de terapia intensiva es importante estimar el riesgo de muerte en los pacientes ingresados para así redirigir metas en el manejo de los mismos. Sin embargo, la falta de consistencia y la subjetividad del clínico han sido factores determinantes para el desarrollo de escalas de mortalidad con el fin de lograr mediciones cuantitativas certeras. Existen muchas escalas, índices y biomarcadores desarrollados con el fin de predecir mortalidad. Entre estos se encuentra la escala PIM-2, el índice de choque y el lactato. Objetivo: Comparar la escala PIM-2, el índice de choque y el lactato como marcadores precoces de mortalidad en los niños con choque séptico. Metodología: Se realizó un estudio de cohorte prospectivo, en el cual se incluyeron todos los pacientes con criterios de choque séptico que ingresaron a la Unidad de Terapia intensiva del Hospital del Niño entre agosto del 2015 y marzo del 2016. Se realizaron los cálculos de PIM-2, índice de choque y valor de lactato al ingreso en los pacientes sobrevivientes y fallecidos y se compararon los resultados de estos marcadores como predictores de mortalidad. Resultados: La escala PIM-2 resultó un excelente predictor de mortalidad con un área bajo la curva de 94% comparada con el índice de choque que osciló entre 53% a 61% y el valor de lactato que fue de 77%. Conclusión: El PIM-2, resultó una prueba sencilla, gratuita y fácil de calcular, con una excelente sensibilidad para la predicción de mortalidad en niños críticos con diagnóstico de choque séptico. A pesar de la facilidad de cálculo del índice de choque, este resultó ser un pobre predictor de mortalidad. El lactato es un marcador aceptable para predecir mortalidad, sin embargo, debe correlacionarse con otras escalas ya que puede ser sesgado por otras causas que produzcan su aumento o disminución.

Summary: In the pediatric population, septic shock is an entity associated with high mortality and morbidity rates. In the intensive care unit, it is important to estimate the risk of death of the patients admitted in order to re-direct the goals of treatment. However, the lack of consistency and the subjectivity of the clinician have been determinant factors for the development of mortality scales with the purpose of achieving accurate quantitative measurements. Many scales, indexes and biomarkers exist which have been developed to predict mortality. Among these are the PIM-2 scale, the shock index and serum lactate. Objective: To compare the PIM-2 scale, the shock index and serum lactate as early markers of mortality in children with septic shock. Methods: A prospective cohort study was performed in which all patients with septic shock criteria admitted to the intensive care unit of the Hospital del Niño between August 2015 and March 2016 were included. Calculations of PIM-2, shock index and serum lactate value at admission of the surviving and the deceased patients were performed, and the results of these markers were compared as predictors of mortality. Results: The PIM-2 scale resulted in an excellent mortality predictor with an under the curve area of 94% compared to the shock index which oscillated between 53 and 61%, and the value of lactate which was of 77%. Conclusion: The PIM-2 scale turned out to be a simple, free and easy to calculate test, with an excellent sensibility to predict mortality in critically ill children with septic shock. Despite the ease of use of the shock index, it resulted to be a poor predictor of mortality. However, it should be correlated with other scales since it can be biased by other causes which produce its increase or decrease.

Incubadora neonatal con ventilación mecánica embebida / Mechanical Ventilation embedded in Neonatal Incubator

RESUMEN Se presenta un equipo de soporte de vida neonatal (ESVIN) que emplea la terapia térmica y terapia ventilatoria (neumática) en un solo equipo para proveer ventilación pulmonar con aire caliente, humedecido y enriquecido con oxígeno, en un ambiente caliente, humidificado y estéril. El equipo es capaz de simultáneamente dar ventilación pulmonar e incubar, siendo una de sus características principales la minimización de la condensación del agua en el corrugado y ofrece la característica adicional de evitar la movilización y/o desconexión del neonato para realizar ciertos procedimientos tales como: cirugías e intubaciones, entre otras. Los principales resultados son el tiempo de acceso al neonato menor a 2 s y minimización de la condensación de agua. Asimismo, los resultados del control térmico son de tiempo de estabilización en el habitáculo de 75 minutos para la temperatura de 36 °C y tiempo de estabilización de la temperatura de la piel del neonato de 58 minutos.

ABSTRACT A neonatal life support equipment (ESVIN) employing simultaneously thermal therapy and ventilatory (pneumatic) therapy is presented in a single kit to provide pulmonary ventilation with warm, moistened and oxygen enriched air in a warm, humidified and sterile environment. The invention behind ESVIN provided simultaneously pulmonary ventilation and incubation having optimized the minimization of water condensation in the corrugated pipe and offered the additional feature of avoiding the mobilization and / or disconnection of the neonate to perform certain procedures such as: surgeries and intubations, among others. ESVIN has an access to newborns of less than 2 s and non-visible water condensation. The main results in thermal control were a stabilization time in the newborn compartment of 75 minutes for the temperature of 36 °C and a stabilization of the temperature of the skin of the neonate of 58 minutes.

Identification of new type I interferon-stimulated genes and investigation of their involvement in IFN-β activation

Virus infection induces the production of type I interferons (IFNs). IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes (ISGs). ISGs play very important roles in innate immunity through a variety of mechanisms. Although hundreds of ISGs have been identified, it is commonly recognized that more ISGs await to be discovered. The aim of this study was to identify new ISGs and to probe their roles in regulating virus-induced type I IFN production. We used consensus interferon (Con-IFN), an artificial alpha IFN that was shown to be more potent than naturally existing type I IFN, to treat three human immune cell lines, CEM, U937 and Daudi cells. Microarray analysis was employed to identify those genes whose expressions were up-regulated. Six hundred and seventeen genes were up-regulated more than 3-fold. Out of these 617 genes, 138 were not previously reported as ISGs and thus were further pursued. Validation of these 138 genes using quantitative reverse transcription PCR (qRT-PCR) confirmed 91 genes. We screened 89 genes for those involved in Sendai virus (SeV)-induced IFN-β promoter activation, and PIM1 was identified as one whose expression inhibited SeV-mediated IFN-β activation. We provide evidence indicating that PIM1 specifically inhibits RIG-I- and MDA5-mediated IFN-β signaling. Our results expand the ISG library and identify PIM1 as an ISG that participates in the regulation of virus-induced type I interferon production.

PIM Kinase as an Executional Target in Cancer

PIM (proviral integration site for moloney murine leukemia virus) kinase plays a key role as an oncogene in various cancers including myeloma, leukemia, prostate and breast cancers. The aberrant expression and/or activation of PIM kinases in various cancers follow an isoform-specific pattern. While PIM1 is predominantly expressed in hematological and solid tumors, PIM2 and PIM3 are largely expressed in leukemia and solid tumors, respectively. All of PIM kinases cause transcriptional activation of genes involved in cell survival and cell cycle progression in cancer. A variety of pro-tumorigenic signaling molecules, such as MYC, p21(Cip1/Waf1)/p27(kip1), CDC25, Notch1 and BAD have been identified as the downstream targets of PIM kinases. So far, three kinds of adenosine triphosphate-competitive PIM inhibitors, SGI-1776, AZD1208, and LGH447 have been in clinical trials for the treatment of acute myelogenous leukemia, prostate cancer, lymphoma, or multiple myeloma. This review sheds light on the signaling pathways involved in the PIM kinase regulation and current status of developing PIM kinase inhibitors as clinical success in combating human cancer.

Simultaneous Determination of 4 Components in Xinyi Biyan Pills by HPLC-switching Wavelength Method / 中国药房

OBJECTIVE: To establish the method for simultaneous determination of pim-O-glucosylcimifugin, liquiritin, 5-0-methylvisammioside and amonium glycyrrhizinate in Xinyi byan pills.METHODS: HPLC-switching wavelength method was used for content determination of 52 batches of Xinyi byan pills sample from enterprises A, B, C. The determination was performed on Kromasil C18 column with mobile phase consisted of acetonitrile-0. 1 ％ phosphoric acid at the flow rate of 1. 0 mL/min. The detection wavelengths were set at 220 nm (pim-O-glucosylcimifugin, liquiritin, 5-O-methylvisammioside) and 250 nm (amonium glycyrrhizinate). The column temperature was 30℃, and sample size was 10 μ L. RESULTS: The linear ranges of prim-O-glucosylcimifugin, liquiritin, 5-O-methylvisammioside and amonium glycyrrhizinate were 6. 138-122. 77 μg/mL (r=0. 999 9), 2. 502-50. 03 μg/mL (r=0. 999 9), 5. 988-119. 75 μg/mL (r=0. 999 9) and 12. 788-255. 76 μg/mL (r=0. 999 9), respectively. RSDs of precision, stability and reproducibility tests were all lower than 2. 0％ (n=6). The recovery rate were 100. 32％ (RSD=0. 58％, n=6), 100. 24％ (RSD=0. 56％, n=6), 101. 28％ (RSD=0. 91％, n=6) and 101. 48％ (RSD=0. 79％, n=6), respectively. Total contents of 4 components in enterprise A were generally higher than enterprises B, C, among which the difference of liquiritin was significant; the content of prim-O-glucosylcimifugin in enterprise B was higher than enterprises A, C, while the content of 5-O-methylvisammioside was lower than enterprises A, C. The content of liquiritin in enterprise B was outlier. CONCLUSIONS: This method is simple, reproducible and can provide reference for quality control of Xinyi biyan pills.

Expression of Pim-1 in hepatocellular carcinoma patients and its relationship with oncogene c-Myb / 国际外科学杂志

Objective To determine the expression of Pim-1 in hepatocellular carcinoma patients and its relationship with oncogene c-Myb.Methods From January 2009 to October 2013,136 patients with hepatocellular carcinoma (HCC) who were received surgical treatment at department of hepatobiliary surgery,the first affiliated hospital of the fourth military medical university,were selected to collect the clinical data,resected liver cancer tissues and para cancerous tissues,and complete the follow-up work.The patients were followed up by outpatient review or telephone.The deadline for follow-up was June 28,2017.To the end of the study,14 cases were lost,and 122 cases of HCC were included in this study.At the same time,85 cases of normal liver tissues which were obtained from hepatic hemangioma in the same period were collected as normal control group.The expression of Pim-1 and c-Myb protein detected in these liver tissues was detected by immuno-histochemical (IHC) staining.Western-blotting test was used to detect the expression of Pim-1 protein in human hepatoma cells SMMC-7721,HepG2,Hep3B,Huh7,MHCCL,MHCC-97H and normal human hepatocytes L-02,HL-7702.The average number of two samples was compared by Student's t test.The count data were analyzed by chi-square test or Spearman correlation analysis.Results The total positive expression rate of Pim-1 protein in liver cancer tissues was 88.5％ (108/122),which was significantly higher than that of para cancerous tissues 73.0％ (89/122) and normal liver tissues 69.4％ (59/85) (x2 =9.513,P =0.003;x2 =11.739,P =0.001).The total positive expression rate of c-Myb was 96 cases,of which 88 cases were positive for Pim-1 and c-Myb.Spearman correlation analysis showed that the expression of Pim-1 protein and c-Myb protein in HCC tissues was positively correlated (r =0.107,P =0.037).Compared with L-02 and HL-7702 cells,the content of Pim-1 in the cells of human hepatoma cells SMMC-7721,HepG2,Hep3B,Huh7,MHCCL,MHCC-97H increased significantly (P ＜0.01).Conclusions The expression level of Pim-1 in hepatocellular carcinoma tissues and hepatocellular carcinoma cells increased significantly,and it was correlated positively with the expression of proto oncogene c-Myb.This is closely related to the occurrence and development of HCC.

Effects of Pim-1 inhibitor on mouse model of inflammatory bowel disease induced by TNBS / 中南大学学报(医学版)

Objective:To explore the role of Pim-1 in the pathology of inflammatory bowel disease and the potential effect of Pim-1 inhibitor on treating such disease.Methods:Forty-five BALB/c mice were randomly divided into 5 groups (n=9):A normal control group,a inflammatory bowel disease group,two different dose of Pim-1 inhibitor treatment groups,and steroidhormone treatment group.The model of inflammatory bowel disease was induced by intracolonic administration of 2,4,6-trinitrobenzenestdfonic acid (TNBS) and ethanol mixture.Mice were treated with Pim-1 inhibitor [intraperitoneal inject,5 or 10 mg/(kg.d)] for 5 days and prednisone (intragastric administration,0.1 mg/d) for 5 days.The DAI,colon length,gross score and pathological grade were evaluated.The expressions ofT cell master transcription factors T-box expressed in T cells (T-bet),GATA binding protein 3 (GATA-3),RA orphan receptorγ (RORyt)and forkhead box P3 (Foxp3) were measured by Real-time PCR and Western blot,respectively.Results:Pim-1 inhibitor and prednisone showed therapeutic effect on acute TNBS colitis in vivo.GATA3 and RORγt were significantly up-regulated in acute TNBS colitis (P＜0.05).In contrast,the expression of Foxp3 was suppressed in the inflammatory bowel disease group,whereas it did not cause any significant change in T-bet expression (P＞0.05).Administration of Pim-1 inhibitor and prednisone resulted in suppression of GATA3,RORγt expression,and the increase of Foxp3 expression (P＜0.05).Administration of Pim-1 inhibitor and prednisone resulted in inhibition of T-bet mRNA expression (P＜0.05),but only prednisone could inhibit T-bet protein expression (P＞0.05).Conclusion:Pim-1 inhibitor significantly suppresses Th2-and Th17-type immune responses.Furthermore,Pim-1 inhibitor could induce T-cell differentiation towards a Treg phenotype.Pim-1 inhibitor has therapeutic effect on acute TNBS colitis.