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Resistance to epidermal growth factor receptor-tyrosin kinase inhibitors (TKIs, e.g. icotinib) remains a major clinical challenge. Non-small cell lung cancer patients with wild-type EGFR and/or K-RAS mutation are primary resistance to EGFR-TKIs. Berberine has been found to have potent anticancer activities via distinct molecular mechanism. In this study, we sought to investigate the therapeutic utility of BBR in combination with icotinib to overcome icotinib resistance in NSCLC cells, and explore the molecular mechanism of synergism of icotinib and BBR to EGFR-resistant NSCLC cells. We used the two EGFR-resistant NSCLC cell lines H460 and H1299 for testing the inhibitory effect of icotinib and/or BBR on them. Moreover, xenograft mouse model was applied for assessing the anti-tumor activities of BBR and icotinib in combination. Results showed that BBR and icotinib have a synergistic inhibitory effect on H460 and H1299 cells through induction of autophagic cell death and apoptosis. Accordingly, the anti-cancer effect of BBR plus icotinib was further confirmed in the NSCLC xenograft mouse models. Combination of BBR and icotinib significantly inhibited the protein expression and the activity of EGFR by inducing autophagic EGFR degradation. BBR plus icotinib resulted in intracellular ROS accumulation, which could mediated autophagy and apoptosis and involved in the suppression of cell migration and invasion. In conclusions, combination application of BBR and icotinib could be an effective strategy to overcome icotinib resistance in the treatment of NSCLC.
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Muerte Celular Autofágica , Berberina , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Apoptosis , Berberina/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Éteres Corona , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones , Quinazolinas , Transducción de SeñalRESUMEN
Although chemotherapeutic regimen containing gemcitabine is the first-line therapy for advanced lung squamous cell carcinoma (LSCC), gemcitabine resistance remains an important clinical problem. Some studies suggest that overexpressions of ribonucleotide reductase (RNR) subunit M2 (RRM2) may be involved in gemcitabine resistance. We used a novel RRM2 inhibitor, GW8510, as a gemcitabine sensitization agent to investigate the therapeutic utility in reversing gemcitabine resistance in LSCC. Results showed that the expressions of RRM2 were increased in gemcitabine intrinsic resistant LSCC cells upon gemcitabine treatment. GW8510 not only suppressed LSCC cell survival, but also sensitized gemcitabine-resistant cells to gemcitabine through autophagy induction mediated by RRM2 down-regulation along with decrease in dNTP levels. The combination of GW8510 and gemcitabine produced a synergistic effect on killing LSCC cells. The synergism of the two agents was impeded by addition of autophagy inhibitors chloroquine (CQ) or bafilomycin A1 (Baf A1), or knockdown of the autophagy gene, Bcl-2-interacting protein 1 (BECN1). Moreover, GW8510-caused LSCC cell sensitization to gemcitabine through autophagy induction was parallel with impairment of DNA double-strand break (DSB) repair and marked increase in cell apoptosis, revealing a cross-talk between autophagy and DNA damage repair, and an interplay between autophagy and apoptosis. Finally, gemcitabine sensitization mediated by autophagy induction through GW8510-caused RRM2 down-regulation was demonstrated in vivo in gemcitabine-resistant LSCC tumor xenograft, further indicating that the sensitization is dependent on autophagy activation. In conclusion, GW8510 can reverse gemcitabine resistance in LSCC cells through RRM2 downregulation-mediated autophagy induction, and GW850 may be a promising therapeutic agent against LSCC as it combined with gemcitabine.
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Autofagia/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Indoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Ribonucleósido Difosfato Reductasa/antagonistas & inhibidores , Animales , Antimetabolitos Antineoplásicos/farmacología , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Desoxicitidina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos NOD , Ribonucleósido Difosfato Reductasa/fisiología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
PURPOSE: The effects of Shenfu injection on protecting the intestinal mucosal barrier were investigated in rats with sepsis. METHODS: Severe sepsis was established by cecal ligation and puncture (CLP) in 30 healthy Sprague-Dawley rats. Twelve rats that received sham surgery received 10 mL/kg of normal saline. Rats with CLP were randomized to receive 10 mL/kg of normal saline (n = 12) and 5 mL/kg Shenfu (n = 12), and 10 received 10 mL/kg Shenfu injection (n = 12) by tail intravenous injection. Rats were killed after 8 hours. Serum levels of tumor necrosis factor α and interleukin-10, and ileal malondialdehyde and superoxide dismutase activity were measured by enzyme-linked immunosorbent assay. Ileum tissue structures and pathological score were observed by microscopy. Ileal mucosal epithelial cell apoptosis index was calculated by TUNEL assay. Ileal proapoptotic protein Bax, antiapoptotic protein Bcl-2, and tight junction transmembrane protein occludin were measured by immunohistochemistry and immunoblot. RESULTS: The level of tumor necrosis factor α, the ileal malondialdehyde level, ileum pathological score, apoptosis index of ileal mucosal epithelial cells, and Bax protein level were significantly higher, and serum level of interleukin-10, the ileal superoxide dismutase activity, Bcl-2 protein level, Bcl-2/Bax ratio, and occludin protein level were significantly lower in the CLP group than in the sham group (P < .01 or P < .05). Both low- and high-dose Shenfu significantly ameliorated these changes (P < .01 or P < .05), but high-dose injection achieved more significant improvements than did the low-dose injection (P < .01 or P < .05). CONCLUSIONS: Shenfu injection might ameliorate the mucosal barrier function in a model of sepsis in rats in a dose-dependent manner.
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Medicamentos Herbarios Chinos/administración & dosificación , Íleon/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/patología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Modelos Animales de Enfermedad , Femenino , Íleon/metabolismo , Íleon/patología , Inyecciones Intravenosas , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Malondialdehído/metabolismo , Ratas , Ratas Sprague-Dawley , Sepsis/metabolismo , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To explore the expression of Ghrelin and high mobility group protein B1 (HMGB1) in the serum and the intestinal tissue of sepsis model rats, and to evaluate the effect of electro-acupuncture (EA) at Zusanli (ST36) on the expression of HMGB1 and Ghrelin. METHODS: Forty-eight male Wistar rats were randomly divided into four groups, i.e., the sham-operation (sham), the cecal ligation and puncture group (CLP), the CLP + EA at Zusanli (ST36) group (EA), and the CLP + Ghrelin receptor blocking agent + EA group (GHSRA), 12 in each group. A sepsis rat model was prepared by CLP. The incision of the abdominal wall was immediately sutured along the ventral midline for rats in the Sham group. In the EA group EA at Zusanli (ST36) was performed 20 min after CLP surgery with the constant voltage (2 - 100 Hz, 2 mA) for 30 min. In the GHSRA group, Ghrelin receptor blocking agent, [D-Arg1, D-Phe5, D-Trp79, Leu11]-substance P (700 nmol/kg), was administered through intravenous injection immediately after CLP, and 20 min later, EA at Zusanli (ST36) was performed in the same way as for rats in the EA group. Blood samples were withdrawn 12 h after CLP. The serum levels of Ghrelin and HMGB1 were detected using ELISA. Ghrelin expressions and the number of Ghrelin immunopositive cell in the jejunum were determined by immunohistochemistry. HMGB1 contents of the jejunum tissue were detected by Western blotting. RESULTS: Compared with the Sham group, the number of serum immunopositive cells and the expression of HMGB1 in the jejunum tissue significantly increased and levels of Ghrelin and the expression rate of immunopositive cells significantly decreased in the CLP group (P < 0.05). Compared with the CLP group, the number of serum immunopositive cells and the expression of HMGB1 in the jejunum tissue significantly decreased, but levels of Ghrelin and the expression rate of immunopositive cells significantly increased in the EA group (P < 0.05). Compared with the EA group, the number of serum immunopositive cells and the expression of HMGB1 in the jejunum tissue significantly increased in the GHSRA group (P < 0.05), but there was no statistical difference in levels of Ghrelin between the two groups (P > 0.05). The serum level of HMGB1 was negatively correlated with Ghrelin in the Sham group, the CLP group, and the EA group (r = -0. 528, P < 0.01). CONCLUSIONS: EA at Zusanli (ST36) could inhibit the expression of HMGB1 in the jejunum of septic rats, and promote the expression of Ghrelin. The expression of HMGB1 was inhibited by Ghrelin receptor blocking agent, which suggested that the anti-inflammation of EA at Zusanli (ST36) might be associated with Ghrelin.
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Electroacupuntura , Ghrelina/metabolismo , Proteína HMGB1/metabolismo , Sepsis/metabolismo , Animales , Modelos Animales de Enfermedad , Yeyuno/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Extreme endurance athletic challenges provide unique opportunities to study the cardiovascular system's capacity for structural, functional, and hemodynamic adaptation. The authors present a case of a male subject who ran 2,469 km, with serial multiparametric cardiac magnetic resonance imaging used to demonstrate adaptive and maladaptive alterations in cardiac remodeling and myocardial tissue health. (Level of Difficulty: Advanced.).
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BACKGROUND: Sepsis is a major medical challenge. Magnolol is an active constituent of Houpu that improves tissue function and exerts strong anti-endotoxin and anti-inflammatory effects, but the mechanism by which it reduces intestinal inflammation in sepsis is yet unclear. AIM: To assess the protective effect of magnolol on intestinal mucosal epithelial cells in sepsis and elucidate the underlying mechanisms. METHODS: Enzyme-linked immunosorbent assay was used to measure tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and regulated on activation, normal T-cell expressed and secreted (RANTES) levels in serum and ileal tissue in animal studies. The histopathological changes of the ileal mucosa in different groups were observed under a microscope. Cell Counting Kit-8 and cell permeability assays were used to determine the concentration of drug-containing serum that did not affect the activity of Caco2 cells but inhibited lipopolysaccharide (LPS)-induced decrease in permeability. Immunofluorescence and Western blot assays were used to detect the levels of RANTES, inhibitor of nuclear factor kappa-B kinase ß (IKKß), phosphorylated IKKß (p-IKKß), inhibitor of nuclear factor kappa-B kinase α (IκBα), p65, and p-p65 proteins in different groups in vitro. RESULTS: In rats treated with LPS by intravenous tail injection in the presence or absence of magnolol, magnolol inhibited the expression of proinflammatory cytokines, IL-1ß, IL-6, and TNF-α in a dose-dependent manner. In addition, magnolol suppressed the production of RANTES in LPS-stimulated sepsis rats. Moreover, in vitro studies suggested that magnolol inhibited the increase of p65 nucleation, thereby markedly downregulating the production of the phosphorylated form of IKKß in LPS-treated Caco2 cells. Specifically, magnolol inhibited the translocation of the transcription factor nuclear factor-kappa B (NF-κB) from the cytosol into the nucleus and down-regulated the expression level of the chemokine RANTES in LPS-stimulated Caco2 cells. CONCLUSION: Magnolol down-regulates RANTES levels by inhibiting the LPS/NF-κB signaling pathways, thereby suppressing IL-1ß, IL-6, and TNF-α expression to alleviate the mucosal barrier dysfunction in sepsis.
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Lymphadenopathy is an important characteristic of POEMS syndrome, and a Castleman disease (CD)-like pathologic change in the lymph nodes is one of the major diagnostic criteria. However, the characteristics of lymphadenopathy in POEMS still have not been completely elucidated. The lymph node biopsies are available only for a small proportion of patients. A simple and safe way is needed to rule CD in or out. This study aimed to analyse the features of lymphadenopathy and estimate the role of imaging methods, including computed tomography (CT) and positron emission tomography-CT (PET/CT), in the diagnosis of lymphadenopathy in patients with POEMS syndrome. We conducted a retrospective analysis of 23 patients with confirmed POEMS syndrome. All of the patients received chest and abdominal CT scan and/or superficial ultrasound examinations. Four patients underwent PET/CT examinations, and 6 patients received lymph node biopsies. Enlarged lymph nodes (short diameter ≥ 1 cm) were found in 48% (11/23) of patients, but only 1 patient had an enlarged lymph node with a diameter ≥ 2 cm. Lymph nodes with CD-like pathologic changes from 2 patients showed increased maximum standard uptake values (SUVmax) of 18F-deoxyglucose (18FDG) on PET/CT, while lymph nodes with reactive pathologic changes from 2 other patients showed a normal metabolic PET/CT profile. The extent of lymph node enlargement in patients with POEMS was less than that in patients with CD per se. We draw the conclusion that most of the enlarged lymph nodes had diameters ≤ 2 cm, which is less than that in cases of CD per se and PET/CT may be helpful in determining whether enlarged lymph nodes are characterized by CD-like changes or not.
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Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs). In this study, we assessed whether the combination of bisdemethoxycurcumin (BDMC) and icotinib could surmount primary EGFR-TKI resistance in NSCLC cells and investigated its molecular mechanism. Results showed that the combination of BDMC and icotinib produced potently synergistic growth inhibitory effect on primary EGFR-TKI-resistant NSCLC cell lines H460 (EGFR wild-type and K-ras mutation) and H1781 (EGFR wild-type and Her2 mutation). Compared with BDMC or icotinib alone, the two drug combination induced more significant apoptosis and autophagy via suppressing EGFR activity and interaction of Sp1 and HDCA1/HDCA2, which was accompanied by accumulation of reactive oxygen species (ROS), induction of DNA damage, and inhibition of cell migration and invasion. ROS inhibitor (NAC) and autophagy inhibitors (CQ or 3-MA) partially reversed BDMC plus icotinib-induced growth inhibitory effect on the NSCLC cells. Meanwhile, co-treatment with NAC attenuated the two drug combination-induced autophagy, apoptosis, DNA damage and decrease of cell migration and invasion ability. Also, 3-MA or CQ can abate the combination treatment-induced apoptosis and DNA damage, suggesting that there is crosstalk between different signaling pathways in the effect produced by the combination treatment. Our data indicate that BMDC has the potential to improve the treatment of primary EGFR-TKI resistant NISCLC that cannot be controlled with single-target agent, such as icotinib.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/uso terapéutico , Diarilheptanoides/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Daño del ADN , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción Sp/antagonistas & inhibidores , Canal Aniónico 1 Dependiente del Voltaje/antagonistas & inhibidoresRESUMEN
PURPOSE: The objective of this study was to retrospectively research the clinical characteristics, pathogen distribution, prognosis of nosocomial bloodstream infection (nBSI), and the associated risk factors for nBSI. MATERIALS AND METHODS: The clinical and microbiological data of patients with nBSI were retrospectively studied. Patients were treated at the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Hangzhou, China) between January 2013 and December 2016. RESULTS: Our study spanned a four-year period and included 704 episodes of nBSI. The incidence rate was 4.11 per 1000 admissions. Of these cases, 96.7% were monomicrobial: gram-negative bacteria (56.4%), gram-positive bacteria (33.4%), and fungal (7%). Of all the Escherichia coli isolates, 41.5% were extended-spectrum ß-lactamase-producing (ESBL)-positive. Of the Klebsiella pneumoniae isolates, 50.9% were resistant to imipenem. Of the Staphylococcus aureus isolates, 42.1% were methicillin-resistant. The overall 28-day mortality rate in all patients with nBSI was 24.4%. Parenteral nutrition (PN) and sequential organ failure assessment (SOFA) scores (≥5) were closely related to the 28-day mortality rate of nBSI, while removal of venous catheters and appropriate empirical therapy were protective factors of 28-day mortality. CONCLUSIONS: Gram-negative bacteria predominantly developed in nBSI. Timely removal of venous catheters (catheter retention timeâ¯≥â¯7â¯days) and implementation of appropriate empirical therapy improved the nBSI outcomes.
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Bacteriemia/epidemiología , Infección Hospitalaria/epidemiología , Mortalidad Hospitalaria , Adulto , Anciano , Bacteriemia/microbiología , China/epidemiología , Infección Hospitalaria/microbiología , Escherichia coli , Femenino , Hongos , Hospitalización , Humanos , Klebsiella pneumoniae , Masculino , Staphylococcus aureus Resistente a Meticilina , Persona de Mediana Edad , Nutrición Parenteral/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Staphylococcus aureusRESUMEN
The purpose of this study was to examine the association between serum uric acid (sUA) and the incidence of hypertension in nonmetabolic syndrome (non-MetS) subjects.This was a prospective observational study including 23,525 subjects who had been followed up for at least 5 years. A logistic regression model was used to assess independent risk factors associated with hypertension. An area under the receiver operating characteristic curve (auROC) was generated, and a nomogram was developed to assess diagnostic ability of sUA and the sUA-based score.We enrolled 11,642 subjects, and 763 (6.55%) were diagnosed with hypertension at the 5-year follow-up. Subjects were classified into 4 groups based on the sUA quarter. Using Q1 as the reference group, Q2, Q3, and Q4 were found to show a higher risk for the development of hypertension with odds ratio of 1.51 (1.15, 1.98), 1.72 (1.30, 2.27), and 2.27 (1.68, 3.06), respectively (Pâ<â.001) after adjusting for other known confounding variables. Interaction analysis showed that there was no significant difference between subgroups stratified on the basis of sex, age, body mass index, fasting plasma glucose, and high-density lipoprotein cholesterol except triglycerides (Pâ=â.006). The auROCs for sUA and the sUA-based score were 0.627 (0.607, 0.647) and 0.760 (0.742, 0.777), respectively. A nomogram comprising independent risk factors was developed to predict the 5-year risk of hypertension for each subject.High sUA was significantly associated with the incidence of hypertension in non-MetS subjects adjusting for confounders.
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Hipertensión , Hiperuricemia , Ácido Úrico , Adulto , China/epidemiología , Femenino , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Factores de Riesgo , Ácido Úrico/análisis , Ácido Úrico/sangreRESUMEN
Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, is a major clinical problem in the treatment of patients with non-small cell lung cancer (NSCLC). YM155 is a survivin small molecule inhibitor and has been demonstrated to induce cancer cell apoptosis and autophagy. EGFR-TKIs have been known to induce cancer cell autophagy. In this study, we showed that YM155 markedly enhanced the sensitivity of erlotinib to EGFR-TKI resistant NSCLC cell lines H1650 (EGFR exon 19 deletion and PTEN loss) and A549 (EGFR wild type and KRAS mutation) through inducing autophagy-dependent apoptosis and autophagic cell death. The effects of YM155 combined with erlotinib on apoptosis and autophagy inductions were more obvious than those of YM155 in combination with survivin knockdown by siRNA transfection, suggesting that YM155 induced autophagy and apoptosis in the NSCLC cells partially depend on survivin downregulation. Meanwhile, we found that the AKT/mTOR pathway is involved in modulation of survivin downregulation and autophagy induction caused by YM155. In addition, YM155 can induce DNA damage in H1650 and A549 cell lines. Moreover, combining erlotinib further augmented DNA damage by YM155, which were retarded by autophagy inhibitor 3MA, or knockdown of autophagy-related protein Beclin 1, revealing that YM155 induced DNA damage is autophagy-dependent. Similar results were also observed in vivo xenograft experiments. Therefore, combination of YM155 and erlotinib offers a promising therapeutic strategy in NSCLC with EGFR-TKI resistant phenotype.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Clorhidrato de Erlotinib/farmacología , Imidazoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Naftoquinonas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Survivin/metabolismoRESUMEN
OBJECTIVE: To observe the effect of intensive insulin therapy on improving the condition of critically ill patients. METHODS: A prospective, randomized, controlled study involving adults receiving mechanical ventilation was performed. On admission, critically ill patients were randomly assigned to receive intensive insulin therapy (infusion of insulin only if the blood glucose level exceeded 6.1 mmol/L and maintenance of blood glucose at a level 4.4-6.1 mmol/L, IT group) and conventional treatment (infusion of insulin only if the blood glucose level exceeded 11.9 mmol/L and maintenance of blood glucose at a level 10.0-11.1 mmol/L, CT group). The blood glucose was detected every 4 hours. The days of stay in the intensive care unit (ICU), time of the ventilatory support needed, the time for retention of tracheal intubation, the morning blood glucose level (6 am), the intake of nonprotein calories per day, the dosage of required insulin per day,therapeutic intervention scoring system-28 (TISS-28) score,human leukocyte antigen (locus) DR (HLA-DR), CD4+/CD8+, the mortality rate,acute renal failure (serum creatine >221 micromol/L), bilirubinemia (total bilirubin >34.2 micromol/L),the number of patients who received red-cell transfusions,fever (temperature in mouth >38.5 centigrade) and the rate of hypoglycemia were determined and registered. RESULTS: In a total of 116 patients enrolled, intensive insulin therapy reduced mortality rate (44.83 % with conventional treatment, compared with 12.07 % with intensive insulin therapy,P< 0.01). Intensive insulin therapy reduced the days of stay in ICU, TISS-28 score per day, time of the ventilatory support needed, time for retention of tracheal intubation, mean morning blood glucose levels (6 am) compared with those in CT group (P<0.05 or P<0.01), and patients receiving intensive insulin therapy were less likely to require intensive care. Intensive insulin therapy also raised consumption of insulin per day, HLA-DR and CD4+/CD8+ obviously (P<0.05 or P<0.01). Compare with the morbidity between two groups, the incidence of fever due to infection, acute renal failure and red-cell transfusions were higher in CT group (all P<0.01). CONCLUSION: Intensive insulin therapy maintaining blood glucose at a level 4.4-6.1 mmol/L reduces mortality rate among critically ill patients.
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Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Unidades de Cuidados Intensivos , Anciano , Enfermedad Crítica , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
AIM: To investigate the expression of NOS in gastric carcinoma, and to explore the relationship between the expression of nitric oxide synthases (NOS) and p53, PCNA, pathological features and clinical staging of gastric cancer. METHODS: The activity of NOS protein was investigated in 85 samples of human gastric carcinoma and 25 samples of normal gastric mucosal tissue by biochemical assay. We then examined the expression of NOS, p53, PCNA in 85 samples of human gastric cancer was examined by immunohistochemistry, and NOS mRNA expression in 85 gastric cancer tissue specimens by in situ hybridization. RESULTS: Biochemical assay showed that the activity of NOS was significantly higher in gastric carcinoma than in normal gastric mucosal tissues (t = 0.4161, P<0.01). Immunohistochemistry revealed that endothelial nitric oxide synthase (eNOS) expressed in all samples of normal gastric mucosa, but only 6 cases of 85 gastric cancer specimens showed weak positive immunohistochemical reactions to eNOS (20%). Inducible nitric oxide synthase (iNOS) was expressed strongly in human gastric carcinoma (81.2%). In situ hybridization analysis showed that iNOS mRNA expression was significantly stronger than eNOS mRNA expression in gastric cancer tissue (chi(2) = 10.23, P<0.01). The expression of iNOS in gastric cancer was associated with differentiation, clinical stages or lymph node metastases (r = 0.3426, P<0.05). However, iNOS expression did not correlate with histological classifications and morphological types. The expression of iNOS was significantly correlated with p53 or PCNA expression (r = 0.3612, P<0.05). The expression of neuronal nitric oxide synthase (nNOS) was not examined by immunohistochemistry and in situ hybridization in gastric cancer specimens and normal gastric mucosa. CONCLUSION: In human gastric cancer, there is an enhanced expression of iNOS, but not of eNOS. NOS promotes the proliferation of tumor cells and plays an important role in gastric cancer spread. Inactivation of antioncogene p53 and overexpression of iNOS might play a synergetic role in the process of carcinogenesis of human gastric carcinoma.
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Adenocarcinoma/fisiopatología , Óxido Nítrico Sintasa/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Neoplasias Gástricas/fisiopatología , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma/secundario , Adulto , Anciano , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Metástasis Linfática , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Neoplasias Gástricas/patologíaRESUMEN
In many traditional Chinese medicine (TCM) hospitals, most patients are elderly with chronic diseases. Nosocomial bloodstream infections (nBSIs) are an important cause of morbidity and mortality. A retrospective surveillance study was performed to examine the epidemiology and microbiology of nBSIs in a TCM hospital from 2009 to 2011. A total of 482 patients with nBSIs were included in the study period. The incidence rate was 5.7/1000 admissions. Escherichia coli (25.5%) was the most common Gram-negative and coagulase-negative staphylococcus (CoNS) (14.1%) was the most common Gram-positive organism isolated. One-third of the E. coli and Klebsiella pneumoniae isolated from the nBSIs were the third-generation cephalosporin-resistant. Half of the Acinetobacter species isolates were resistant to imipenem. Of all the CoNS isolates, 90.7% were resistant to methicillin. Carbapenems and glycopeptide were the most frequently used for nBSI therapy. Only about one-third of patients (157/482) received appropriate empirical therapy. Septic shock, hemodialysis, Pitt bacteremia score >4, urinary tract infection, and appropriate empirical therapy were most strongly associated with 28-d mortality. The incidence of nBSIs was low in the TCM hospital but the proportion of nBSIs due to antibiotic-resistant organisms was high. A high Pitt bacteremia score was one of the most important risk factors for mortality in nBSIs. Therefore, the implementation of appropriate empirical therapy is crucial to improve the clinical outcome of nBSIs.
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Bacteriemia/epidemiología , Bacteriemia/microbiología , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Acinetobacter , Adulto , Anciano , Anciano de 80 o más Años , Cefalosporinas/química , China , Coagulasa/química , Escherichia coli , Femenino , Humanos , Klebsiella pneumoniae , Masculino , Medicina Tradicional China , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Choque Séptico/metabolismo , Staphylococcus , Resultado del TratamientoRESUMEN
Sepsis results in high morbidity and mortality. Immunomodulation strategies could be an adjunctive therapy to treat sepsis. Acupuncture has also been used widely for many years in China to treat sepsis. However, the underlying mechanisms are not well-defined. We demonstrated here that EA preconditioning at ST36 obviously ameliorated CLP-induced intestinal injury and high permeability and reduced the mortality of CLP-induced sepsis rats. Moreover, electroacupuncture (EA) pretreatment exerted protective effects on intestinal mucosal immune barrier by increasing the concentration of sIgA and the percentage of CD3+, γ/δ, and CD4+ T cells and the ratio of CD4+/CD8+ T cells. Although EA at ST36 treatments immediately after closing the abdomen in the CLP procedure with low-frequency or high-frequency could not reduce the mortality of CLP-induced sepsis in rats, these EA treatments could also significantly improve intestinal injury index in rats with sepsis and obviously protected intestinal mucosal immune barrier. In conclusion, our findings demonstrated that EA at ST36 could improve intestinal mucosal immune barrier in sepsis induced by CLP, while the precise mechanism underlying the effects needs to be further elucidated.
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In a previous study, survivin mRNA expression in non-small cell lung cancer (NSCLC) tissue had been demonstrated to be associated with unfavorable prognosis of patients treated with chemotherapy. In this study, we investigated the survivin mRNA levels in blood of patients with stage IIIA-N2 NSCLC and their association with the efficacy of neoadjuvant chemotherapy (NCT) and disease-free survival (DFS) and overall survival (OS). Blood specimens were collected from 56 patients with stage IIIA-N2 NSCLC before (N0) and after the complete of NCT (N1). Survivin mRNA was measured by real-time quantitative-PCR assay. Receiver operating characteristics curve analysis was undertaken to determine the best cutoff value for survivin mRNA. Results showed that high blood survivin mRNA levels at N0 and N1 were significantly associated with clinical (P = 0.01 and P = 0.008, respectively) and pathologic response (both P = 0.004, respectively). Moreover, the change of blood survivin mRNA levels in these NSCLC patients is associated with the clinical and pathologic response to NCT. Patients with high survivin mRNA levels at N0 and N1 had significantly shorter DFS and OS than those with low survivin mRNA levels (P = 0.021 and P = 0.014, respectively for DFS; P = 0.009 and P = 0.005, respectively for OS). Multivariate analysis demonstrated that high blood survivin mRNA level was an independent predictor for worse DFS and OS in the NSCLC patients receiving NCT. In conclusion, survivin mRNA level in blood from stage IIIA-N2 NSCLC patients receiving NCT is predictive of cancer outcome.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioterapia , Proteínas Inhibidoras de la Apoptosis/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Neoadyuvante , ARN Mensajero/sangre , Anciano , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Survivin , Resultado del TratamientoRESUMEN
The epidermal growth factor receptor (EGFR) mutations have been proven to be a reliable predictive marker for the response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the responses to EGFR-TKIs vary even among patients with EGFR mutation. Recent study showed that survivin overexpression attenuated EGFR-TKI-induced apoptosis and inhibited the antitumor effect of EGFR-TKIs on EGFR mutation NSCLC cells. We investigated the role of survivin mRNA expression in peripheral blood on predicting response and prognosis in NSCLC patients treated with EGFR-TKIs. Survivin mRNA expression levels in blood was detected using quantitative real-time-PCR assay in 62 patients with advanced NSCLC before (D0) and 4 weeks after treatment of EGFR-TKIs (D4w). The associations between survivin mRNA expression in blood and tumor response to treatment, time to progression (TTP), and overall survival (OS) were analyzed. Blood survivin mRNA levels at D0 and D4w were significantly higher in patients with progressive disease than in those with partial response and stable disease. The detections of blood survivin mRNA positivity at D0 and D4w were associated with unfavorable response to EGFR-TKIs treatment and shorter TTP and OS. Multivariate Cox analysis showed that blood survivin mRNA positivity before and 4 weeks after EGFR-TKIs treatment were independent predictor for worse TTP and OS. In conclusion, Blood survivin mRNA positivity was strongly related to a poor treatment outcome of EGFR-TKIs and may be a potential non-invasive biomarker for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/sangre , Receptores ErbB/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Proteínas Inhibidoras de la Apoptosis/sangre , Neoplasias Pulmonares/sangre , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adulto , Anciano , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Survivin , Resultado del TratamientoRESUMEN
OBJECTIVE: To observe the efficacy of electroacupuncture on sepsis and explore its mechanism. METHODS: Fifty cases were randomized into an observation group (26 cases) and a control group (24 cases). The therapeutic programs of anti-infection, anti-shock, respiratory support and nutritional support were provided, but the drugs that might affect gastrointestinal motility were not prescribed in two groups. In the observation group, on the basic treatment as above, electroacupuncture was applied to Zusanli (ST 36), Tianshu (ST 25), Shangjuxu (ST 37), Xiajuxu (ST 39). The excretion ratio of lactulose to mannitol (L/M) in urine and serum D-lactic acid level were detected before and after treatment, as well as the time of target feeding of the patients in two groups. The efficacy was compared between two groups. RESULTS: After treatment for 3 days, L/M was (0.083 +/- 0.020) and serum D-lactic acid was (0.155 +/- 0.196) mmol/L in the observation group, which were apparently reduced as compared with (0.123 +/- 0.034) and (0.193 +/- 0.377) mmol/L in the control group respectively (both P < 0.05). The time of target feeding was (93.69 +/- 27.58) h in the observation group, which was shortened apparently than (118.17 +/- 40.28) h in the control group (P < 0.05). The total effective rate was 80.8% (21/26) in the observation group, which was better than 54.2% (13/24) in the control group (P < 0.05). CONCLUSION: Conventional treatment combined with electroacupuncture can improve intestinal permeability in sepsis patients, recover intestinal function as quickly as possible to achieve target feeding.
Asunto(s)
Electroacupuntura , Mucosa Intestinal/metabolismo , Sepsis/terapia , Puntos de Acupuntura , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Lactulosa/metabolismo , Masculino , Manitol/metabolismo , Persona de Mediana Edad , Permeabilidad , Sepsis/metabolismoRESUMEN
The purposes of this study were to evaluate the treatment outcome of patients with small cell lung cancer (SCLC), focusing on the prognostic factors for response to therapy and overall survival. A retrospective analysis was performed on 116 consecutive patients with SCLC diagnosed from January 1997 to December 2005. Collected data included demographic information, pretreatment clinical assessment, treatment regimen, and outcome information. Prognostic factors were analyzed by log-rank test and Cox regression model. Results showed that performance status (PS) 0-1, limited disease, normal serum carcinoembryonic antigen (CEA), and vascular endothelial growth factor (VEGF) level were associated with improved response rate. The univariate analysis showed that sex, disease extent, PS, serum CEA, and VEGF level significantly influenced overall survival. In multivariate analysis, disease extent, PS, serum CEA, and VEGF level were identified as independent prognostic factors. In addition, prophylactic cranial irradiation (PCI) and number of metastatic sites were independent prognostic factors in limited disease and extensive disease, respectively. We concluded that disease extent, PS, serum CEA, and VEGF level are strong predictors of both response and survival. Female sex was a favorable prognostic factor for survival. Moreover, the prognostic factors for limited disease were good PS, normal serum CEA and VEGF level, and PCI, the prognostic factors for extensive disease were good PS, one metastatic site, normal serum CEA, and VEGF level. The identification of prognostic factors may be useful for the better evaluation of treatment outcome in clinical trials and the use of a targeted and specific treatment.