Fasting plasma glucose and fetal ultrasound predict the occurrence of neonatal macrosomia in gestational diabetes mellitus.

OBJECTIVE: The cause of fetal overgrowth during pregnancy is still unclear. This study aimed to analyze and predict the risk of macrosomia in pregnant women with gestational diabetes mellitus (GDM). METHODS: This study was a retrospective study collected from October 2020 to October 2021. A total of 6072 pregnant women with a routine 75-g oral glucose tolerance test (OGTT) during 24-28 gestational weeks were screened. Nearly equal numbers of pregnant women with gestational diabetes and with normal glucose tolerance (NGT) were included in the study. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curve were performed to determine the index and inflection point for predicting macrosomia occurrence. RESULTS: The data of perinatal outcomes of 322 GDM and 353 NGT who had given birth to single live babies at term were analyzed. We found that significant cut-off values for the prediction of macrosomia are 5.13mmol/L in fasting plasma glucose (FPG), 12.25kg in gestational weight gain (GWG), 3,605g in ultrasound fetal weight gain (FWG) and 124mm in amniotic fluid index (AFI).The area under the ROC curve of this predictive model combined all variables reached 0.953 (95% CI: 0.914 ~ 0.993) with a sensitivity of 95.0% and a specificity of 85.4%. CONCLUSIONS: FPG is positively associated with newborn birth weight. An early intervention to prevent macrosomia may be possible by combining maternal GWG, FPG, FWG, and AFI in gestational diabetes.

Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4-6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2 g/m2) may not be necessary for the moderate-risk patients.

A nomogram prognostic index for risk-stratification in diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study.

BACKGROUND: We aimed to establish a predictive prognostic risk-stratification model for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: The data of 1406 primary DLBCL patients from the Sun Yat-Sen University Cancer Center were analysed to establish a nomogram prognostic index (NPI) model for predicting overall survival (OS) based on pre-treatment indicators. An independent cohort of 954 DLBCL patients from three other hospitals was used for external validation. RESULTS: Age, performance status, stage, lactate dehydrogenase, number of extranodal sites, BCL2, CD5 expression, B symptoms and absolute lymphocyte and monocyte count were the main factors of the NPI model and could stratify the patients into four distinct categories based on their predicted OS. The calibration curve demonstrated satisfactory agreement between the predicted and actual 5-year OS of the patients. The concordance index of the NPI model (0.794) was higher than the IPI (0.759) and NCCN-IPI (0.750), and similar results were obtained upon external validation. For CD5 + DLBCL patients, systemic treatment with high-dose methotrexate was associated with superior OS compared to R-CHOP-based immunochemotherapy alone. CONCLUSIONS: We established and validated an accurate prediction model, which performed better than IPI and NCCN-IPI for prognostic stratification of DLBCL patients.

The role of AMP-activated protein kinase in quercetin-induced apoptosis of HL-60 cells.

Our previous studies have shown that quercetin inhibits Cox-2 and Bcl-2 expressions, and induces human leukemia HL-60 cell apoptosis. In order to investigate the role of AMP-activated protein kinase (AMPK) on quercetin-induced apoptosis of HL-60 cells, we used flow cytometry to detect cell apoptosis. The expressions of LKB1, phosphorylated AMPK (p-AMPK), and Cox-2 protein were detected in HL-60 cells and normal peripheral blood mononuclear cells (PBMCs) by western blot. The expressions of LKB1, p-AMPK, and Cox-2 were detected in HL-60 cells after culture with quercetin. The expressions of p-AMPK were detected in HL-60 cells after culture with AMPK inhibitor Compound C. Then, the expressions of LKB1, p-AMPK, and Cox-2 were detected in HL-60 cells after culture with quercetin alone or quercetin + Compound C. It was found that there was no significant difference in LKB1 between PBMCs and HL-60. p-AMPK in PBMCs was higher than that in HL-60, while Cox-2 was lower. After culture of HL-60 with quercetin, p-AMPK was increased, Cox-2 was decreased, but LKB1 remained unchanged. After culture of HL-60 with Compound C, p-AMPK was decreased. There was no significant difference in LKB1 between the quercetin-alone and the quercetin + Compound C groups. p-AMPK decreased more significantly, while Cox-2 increased more significantly in the quercetin + Compound C groups than those in the quercetin-alone groups. Taken together, these findings suggested that quercetin activates AMPK expression in HL-60 cells independent of LKB1 activation, inhibits Cox-2 expression by activating AMPK, and further regulates the Bcl-2-dependent pathways of apoptosis to exert its anti-leukemia effect.

Risk factors and management of perinatal genital hematoma: A single, tertiary medical center retrospective study in China.

OBJECTIVES: The goal of this study was to identify the risk factors associated with puerperal genital hematoma (PGHA) and analyze the management strategies employed and the resulting maternal outcomes. METHODS: This retrospective cohort study examined the pregnant women delivering vaginally with PGHA in Peking University Third Hospital during January 2002 to December 2021. Exploratory data analysis was performed to assess mean, standard deviation (SD), frequency, percentage and percentiles. Independent-samples t-test was performed for continuous variables. Chi-squared test was performed to compare categorical data. RESULTS: A total of 47 women with PGHA were included, and 94 matched controls were enrolled during the same study period. Compared with the control group, labor induction (34.0% vs. 9.6%, P = 0.000) and episiotomy (66.0% vs. 31.9%, P = 0.000) were more frequently performed in PGHA cases. There was a significantly higher incidence of postpartum hemorrhage (PPH) (53.2% vs. 6.4%, P = 0.000) in PGHA patients than in controls. Compared with the patients with <5 cm hematoma, the proportion of prenatal anemia (25.8% vs. 0.0%, P = 0.027) and the incidence of PPH (67.7% vs. 25.0%, P = 0.005) were significantly higher in patients with ≥5 cm hematoma. In comparison, the active period was significantly shorter (3.1 ± 1.9 vs. 5.1 ± 3.0, P = 0.031) in patients with ≥5 cm hematoma. There were significant differences in perineal pain and swelling (31.3% vs. 67.7%, P = 0.017), vulva hematoma (93.8% vs. 48.4%, P = 0.002) and surgical treatment (62.5% vs. 96.8%, P = 0.002). Nearly half of the patients in the ≥5 cm group underwent secondary suture (41.9% vs. 6.3%, P = 0.011). In patients with PGHA detected after more than 2 h, the body mass index was substantially higher (24.5 ± 4.3 vs. 21.4 ± 2.7, P = 0.011), and the weight gain during pregnancy (14.1 ± 4.3 vs. 11.4 ± 3.5, P = 0.021) was significantly lower. Compared with the patients in PGHA without PPH, age (31.7 ± 4.4 vs. 29.4 ± 2.6, P = 0.033) and newborn birth weight (3367 ± 390 g vs. 3110 ± 419 g, P = 0.045) were considerably higher in PGHA cases with PPH, and the platelet count ([182 ± 44] × 109/L vs. [219 ± 51] × 109/L, P = 0.015) was significantly lower. CONCLUSIONS: Pregnant women who underwent labor induction and episiotomy had a higher incidence of PGHA. The PGHA-related PPH rate is significantly increased. Active surgical treatment is recommended for patients with ≥5 cm hematoma.

Emergence and circulation of enterovirus B species in infants in southern China: A multicenter retrospective analysis.

BACKGROUND: Enteroviruses (EV) are common and can cause severe diseases, particularly in young children. However, the information of EV infection in infants in China is limited due to the vast population size and extensive geographical area of the country. Here, we conducted a retrospective multicenter analysis of available EV data to assess the current epidemiological situation in the infant population in southern China. METHODS: The study enrolled infants with suspected EV infection from 34 hospitals across 12 cities in southern China between 2019 to 2022, and the confirmation of EV was done using RT-PCR and VP1 gene sequencing. RESULTS: Out of 1221 infants enrolled, 330 (27.03%) were confirmed as EV-infected. Of these, 260 (78.79%) were newborns aged 0-28 days. The EV belonged to three species: EV-B (80.61%), EV-A (11.82%), and human rhinovirus (7.58%). Newborns were more susceptible to EV-B than older infants (p < 0.001). Within EV-B, we identified 15 types, with coxsackievirus (CV) B3 (20.91%), echovirus (E) 11 (19.70%), and E18 (16.97%) being the most common. The predominant EV types changed across different years. EV infection in infants followed a seasonal pattern, with a higher incidence from May to August. Furthermore, perinatal mother-to-child EV transmission in 12 mother-newborn pairs were observed. CONCLUSION: Our study is the first to demonstrate the emergence and widespread circulation of EV-B species, mainly CVB3, E11, and E18, in southern China, primarily affecting young infants. This research provides valuable insights for future epidemic assessment, prediction, as well as the elimination of mother-to-child transmission.

Phenomic Imaging.

Human phenomics is defined as the comprehensive collection of observable phenotypes and characteristics influenced by a complex interplay among factors at multiple scales. These factors include genes, epigenetics at the microscopic level, organs, microbiome at the mesoscopic level, and diet and environmental exposures at the macroscopic level. "Phenomic imaging" utilizes various imaging techniques to visualize and measure anatomical structures, biological functions, metabolic processes, and biochemical activities across different scales, both in vivo and ex vivo. Unlike conventional medical imaging focused on disease diagnosis, phenomic imaging captures both normal and abnormal traits, facilitating detailed correlations between macro- and micro-phenotypes. This approach plays a crucial role in deciphering phenomes. This review provides an overview of different phenomic imaging modalities and their applications in human phenomics. Additionally, it explores the associations between phenomic imaging and other omics disciplines, including genomics, transcriptomics, proteomics, immunomics, and metabolomics. By integrating phenomic imaging with other omics data, such as genomics and metabolomics, a comprehensive understanding of biological systems can be achieved. This integration paves the way for the development of new therapeutic approaches and diagnostic tools.

Protocol for Brain Magnetic Resonance Imaging and Extraction of Imaging-Derived Phenotypes from the China Phenobank Project.

Imaging-derived phenotypes (IDPs) have been increasingly used in population-based cohort studies in recent years. As widely reported, magnetic resonance imaging (MRI) is an important imaging modality for assessing the anatomical structure and function of the brain with high resolution and excellent soft-tissue contrast. The purpose of this article was to describe the imaging protocol of the brain MRI in the China Phenobank Project (CHPP). Each participant underwent a 30-min brain MRI scan as part of a 2-h whole-body imaging protocol in CHPP. The brain imaging sequences included T1-magnetization that prepared rapid gradient echo, T2 fluid-attenuated inversion-recovery, magnetic resonance angiography, diffusion MRI, and resting-state functional MRI. The detailed descriptions of image acquisition, interpretation, and post-processing were provided in this article. The measured IDPs included volumes of brain subregions, cerebral vessel geometrical parameters, microstructural tracts, and function connectivity metrics.

[Systematic review and meta-analysis of randomized controlled trials comparing Chinese patent medicines Compound Danshen Dripping Pills and Di'ao Xinxuekang in treating angina pectoris].

BACKGROUND: Chinese patent medicines Compound Danshen Dripping Pills (DSP) and Di'ao Xinxuekang (DXK) capsules were both found effective in treating angina pectoris. However, there is no systematic review comparing their efficacy. OBJECTIVE: This systematic review aims to compare the efficacy of DSP and DXK in treating angina pectoris based on randomized controlled trials (RCTs) comparing their efficacy. SEARCH STRATEGY: RCT reports published between 1994 and 2011 were retrieved from databases including China Doctoral Dissertations Full-text Database, Chinese Journal Full-text Database, China Master's Theses Full-text Database, Wanfang Data, Cochrane Library, Excerpts Medica Database, ScienceDirect, MEDLINE (EBSCOhost) and PubMed. The last retrieval was performed on April 7, 2011. INCLUSION CRITERIA: RCT reports comparing the effects of DSP and DXK were included, regardless publishing language. DATA EXTRACTION AND ANALYSIS: Included RCT reports were assessed for their study quality by using the Jadad scale and the Cochrane risk of bias tool. Data including overall effect and electrocardiography (ECG) improvements were extracted from the included RCTs for meta-analysis. The effect sizes based on overall and ECG diagnosis were measured by odds ratio (OR) and 95% confidence interval (CI). Subgroup analysis and sensitivity analysis were also performed. RESULTS: Nine RCT reports with 926 participants were included. Eight were scored 2 and the other one was scored 4 by using the Jadad scale. The OR between DSP and DXK based on overall diagnosis was 2.06 (95% CI: 1.03-4.12; P(overall)=0.04). Six out of the nine included RCTs reported ECG data. The OR between DSP and DXK based on the ECG diagnosis was 1.92 (95% CI: 1.23-3.00; P(ECG)=0.004). The OR results were stable under subgroup analysis and sensitivity analysis. CONCLUSION: DSP was consistently more effective than DXK according to meta-analysis, which was verified by subgroup analysis and sensitivity analysis. However, more RCTs of higher quality are needed for further confirmation.

Study on the Effects of Individualized Nutritional Intervention on Pregnancy Outcome and Neonatal Immune Function in Patients with Gestational Diabetes Mellitus.

OBJECTIVE: To study the effects of individualized nutritional intervention on pregnancy outcome and neonatal immune function in patients with gestational diabetes mellitus (GDM). METHODS: A retrospective analysis was conducted on 100 GDM patients from the obstetrics and gynecology department of our institute between February 2019 and February 2020. The patients were allocated into the control group given regular intervention and the experimental group given individualized nutritional intervention according to different intervention measures, with 50 cases in each group. The comparison was carried out for patients in the two groups with regard to their modality of delivery, neonatal health, their plasma glucose in fasting state, 2 h after eating, and before bedtime; glycohemoglobin at 8 months of pregnancy, at 9 months of pregnancy, during labor, and 1 month after delivery; their complications; and neonatal CD3+, CD4+, and CD8+ levels. RESULTS: The experimental group outperformed the control group in terms of the spontaneous delivery rate, the number of healthy neonates, and neonatal CD3+, CD4+, and CD8+ levels (P < 0.05). The plasma glucose in fasting state, 2 h after eating, and before bedtime; the glycohemoglobin at 8 months of pregnancy, at 9 months of pregnancy, during labor, and 1 month after delivery; and the incidence of complications of the experimental group were significantly lower than those of the control group (P < 0.05). CONCLUSION: Individualized nutritional intervention increases the rate of spontaneous delivery in GDM patients, enhances neonatal immune function, stabilizes plasma glucose, and reduces complications.

miR-134-5p promotes inflammation and apoptosis of trophoblast cells via regulating FOXP2 transcription in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a prevalent and risky pregnant complication which warrants targeted therapy for restriction the inflammation and apoptosis of trophoblast cells. This study sought to analyze the aberrant expression and regulatory mechanism of microRNA (miR)-134-5p in GDM. The miR-134-5p expression in the serum of GDM patients and normal participants was detected via qRT-PCR, followed by receiver operating characteristic (ROC) curve analysis. In vitro GDM cell model was established in the HTR-8/SVneo cells using 25 mmol/L glucose, followed by transfection with miR-134-5p inhibitor and si-Forkhead box p2(FOXP2). The miR-134-5p and FOXP2 expressions, TNF-α, IL-1ß, and IL-10 levels, cell proliferation, migration, and apoptosis were determined by a combination of qRT-PCR, western blot, ELISA, and cell counting Kit-8, Transwell assay, and flow cytometry. The binding relationship between miR-134-5p and FOXP2 was predicted and verified. Our results revealed that miR-134-5p was increased in the serum of GDM patients and could serve as a critical diagnostic marker for GDM. Moreover, miR-134-5p was upregulated in the high glucose (HG)-induced HTR-8/SVneo cells. The miR-134-5p inhibition suppressed the inflammation and apoptosis of HG-induced HTR-8/SVneo cells. miR-134-5p inhibited FOXP2 expression. FOXP2 expression was decreased in GDM. FOXP2 inhibition attenuated the function of miR-134-5p in HG-induced HTR-8/SVneo cells. Overall, miR-134-5p inhibited the FOXP2 expression to facilitate the inflammation and apoptosis of trophoblast cells, thereby exacerbating GDM.

Using convolutional neural network to analyze brain MRI images for predicting functional outcomes of stroke.

Nowadays, the physicians usually predict functional outcomes of stroke based on clinical experiences and big data, so we wish to develop a model to accurately identify imaging features for predicting functional outcomes of stroke patients. Using magnetic resonance imaging of ischemic and hemorrhagic stroke patients, we developed and trained a VGG-16 convolutional neural network (CNN) to predict functional outcomes after 28-day hospitalization. A total of 44 individuals (24 men and 20 women) were recruited from Taoyuan General Hospital and China Medical University Hsinchu Hospital to enroll in the study. Based on "modified Rankin Scale (mRS)" and "National Institutes of Health Stroke Scale (NIHSS)" assessments, men, women, and mixed men and women were trained separately to evaluate the differences of the results, and we have shown that VGG-16 demonstrated high accuracy in predicting the functional outcomes of stroke patients. The new deep-learning approach has provided an automated decision support system for personalized recommendations and treatments, assisting the physicians to predict functional outcomes of stroke patients in clinical practice.

Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution.

Lymphoma relapse is very common in clinical work, but lineage switch at relapse is rare. Although some cases have reported acute lymphocytic leukemia (ALL) switch to acute myeloid leukemia (AML) or myeloid sarcoma upon relapse, phenotype switch seldom occurs in other types of lymphoma. Here we report six cases with lineage switch from lymphoma to myeloid neoplasms. In our cohort, three cases were mantle cell lymphoma (MCL), and the other three cases were T-cell lymphoblastic lymphoma (T-LBL), B-cell lymphoblastic lymphoma (B-LBL), and diffuse large B-cell lymphoma (DLBCL) at the initial diagnosis. When linage switch occurred, most cases were AML M5 phenotypes, and only one case was myelodysplastic syndrome (MDS) phenotype. 11q23/mixed-lineage leukemia (MLL) rearrangement was negative in all cases. Although intensive therapy and stem cell transplantation have been applied in most cases, the poor outcome cannot be reversed. Therefore, we found that lineage switch could occur not only from ALL to AML or vice versa, but also from MCL or DLBCL to AML. Moreover, the incidence of MLL rearrangement in lineage switch is lower in adult hematologic malignancies as compared with pediatric patients.

Ontogenetic expression and 17ß-estradiol regulation of immune-related genes in early life stages of Japanese medaka (Oryzias latipes).

Accumulating evidence suggests that environmental endocrine disrupting chemicals (EDCs) may exert adverse effects on aquatic organisms via the modulation of immune competence in addition to the endocrine system. However, to date, most studies have been undertaken only on biochemical and histopathological endpoints, and few studies have addressed the role of immune response gene transcript abundance in response to estrogen. In the present study, the ontogenetic expression of immune-related genes, including three complement components (C3-1, C3-2 and Bf/C2), two cytokines (IL-21 and type I IFN [IFN]), lysozyme (LZM), novel immune-type receptor (NITR-18), Ikaros (IK) and ceruloplasmin (CP) were characterized during different developmental periods (from 0 to 28 d post-hatch [dph]) in Japanese medaka. Furthermore, the responses of these genes to natural estrogen (i.e., 17ß-estradiol [E2]) were evaluated. E2 exposure at sublethal concentrations (0.1-10 µg/L) down-regulated the gene expression of C3-1, C3-2, Bf/C2, LZM and CP, while up-regulating the expression of IL-21, IFN, NITR-18 and IK. The results demonstrate a very different trend in gene expression in fish larvae exposed to E2 when compared with the ontogenetic changes in control, suggesting that exposure to environmental chemicals with estrogenic activities may interfere with immune-related genes and thus potentially influence the susceptibility of fish to opportunistic infections. These findings confirm the ability of exogenous estrogens to elicit changes in immune-related gene expression, and broaden our understanding about the mechanisms underlying the actions of EDCs. In addition, the expression profiles of immune-related genes can be developed for use as biomarkers for future immunotoxicological studies.

Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells.

Quercetin is one of the naturally occurring dietary flavonol compounds. It is present abundantly in plants and has chemopreventive and anticancer effects. To investigate its anticancer mechanism, we examined the activity of quercetin against acute leukemia cell line, HL-60. Our results showed that quercetin inhibited cell proliferation and induced apoptosis in a time- and dose-dependent manner. Furthermore, quercetin down-regulated the expression of anti-apoptosis protein Bcl-2 and up-regulated the expression of pro-apoptosis protein Bax. Caspase-3 was also activated by quercetin, which started a caspase-3-depended mitochodrial pathway to induce apoptosis. It was also found that quercetin inhibited the expression of the cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein. Taken together, these findings suggested that quercetin induces apoptosis in a caspase-3-dependent pathway by inhibiting Cox-2 expression and regulates the expression of downstream apoptotic components, including Bcl-2 and Bax. Quercetin can be a potent and promising medicine which might be safely used in leukemia therapy.

[Application effect of respiratory stepwise management in patients with septic shock combined with acute lung injury].

OBJECTIVE: To observe the application effect of respiratory stepwise management in patients with septic shock combined with acute lung injury (ALI). METHODS: 100 patients with septic shock combined with ALI were selected as the research objects in Haikou Hospital Affiliated to Xiangya Medical College of Central South University from January 2018 to June 2020. Fifty patients were given endotracheal intubation or invasive ventilation on the basis of conventional treatment (conventional treatment group). According to the respiratory situation and blood gas, 50 patients were given systematic respiratory support step-by-step treatment according to the principle of simple to complex, and appropriate and scientific respiratory support was given according to the sequence from unarmed to mechanical (respiratory stepwise management group). The differences of cardiac index (CI), central venous pressure (CVP), mean arterial pressure (MAP), extravascular lung water index (EVLWI), arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), oxygenation index (PaO2/FiO2) before and after treatment were compared between the two groups, the therapeutic effects of the two groups were evaluated, and the resuscitation effect, postoperative complications rate, tracheotomy rate, utilization rate of invasive ventilator of the two groups were recorded. RESULTS: After treatment, CI, CVP, EVLWI, PaO2, PaO2/FiO2 levels of the two groups were significantly higher than before treatment, MAP and PaCO2 levels were significantly lower than before treatment; MAP and PaCO2 levels after treatment of the respiratory stepwise management group were significantly lower than those of the conventional treatment group [MAP (mmHg, 1 mmHg = 0.133 kPa): 68.2±7.0 vs. 74.4±6.8, PaCO2 (mmHg): 37.82±4.05 vs. 41.76±4.59], the levels of EVLWI, PaO2 and PaO2/FiO2 in the respiratory stepwise management group were significantly higher than those in the conventional treatment group [EVLWI (mL/kg): 15.34±3.03 vs. 13.64±3.32, PaO2 (mmHg): 84.44±4.83 vs. 79.03±5.54, PaO2/FiO2 (mmHg): 452.42±51.32 vs. 431.73±50.03, all P < 0.05]. There was no significant difference in CI or CVP after treatment between respiratory stepwise management group and conventional treatment group [CI (mL×s-1×m-2): 70.01±21.67 vs. 66.68±18.34, CVP (mmHg): 11.1±3.2 vs. 12.3±3.2, both P > 0.05]. Compared with the conventional treatment group, the average recovery time of the respiratory stepwise management group was earlier (hours: 2.04±0.54 vs. 4.29±0.20, P < 0.05), the stable breathing time was shorter (hours: 3.07±0.22 vs. 5.36±0.35, P < 0.05), the total effective rate and the success rate of recovery were significantly improved [86.0% (43/50) vs. 60.0% (30/50), 94.0% (47/50) vs. 74.0% (37/50), both P < 0.05], the incidence of ventilator associated pneumonia (VAP) and airway complications were significantly reduced [14.0% (7/50) vs. 32.0% (16/50), 12.0% (6/50) vs. 40.0% (20/50), both P < 0.05], and the tracheotomy rate and the utilization rate of invasive ventilator were significantly reduced [8.0% (4/50) vs. 28.0% (14/50), 30.0% (15/50) vs. 60.0% (30/50), both P < 0.05]. CONCLUSIONS: Respiratory stepwise management can effectively improve the resuscitation effect of septic shock patients with ALI, improve cardiopulmonary function, blood gas index and the treatment efficiency, effectively reduce the incidence of iatrogenic trauma and complications.

FGFR1 overexpression renders breast cancer cells resistant to metformin through activation of IRS1/ERK signaling.

Metformin has been suggested as an anti-cancer agent. However, increasing reports show that some tumors are resistant to metformin. Identification of factors affecting metformin mediated cancer therapy is of great significance. FGFR1 is a receptor-tyrosine-kinase that is frequently overexpressed in breast cancer, which is associated with poor-prognosis. To investigate the effect of FGFR1 overexpression on metformin-induced inhibition of breast cancer cells, we demonstrated that FGFR1 overexpression rendered MCF-7 and T47D cells resistant to metformin. In particular, we found that, in addition to AKT and ERK1/2 activation, FGFR1-induced activation of IRS1 and IGF1R, key regulators connecting metabolism and cancer, was associated with metformin resistance. Targeting IRS with IRS1 KO or IRS inhibitor NT157 significantly sensitized FGFR1 overexpressing cells to metformin. Combination of NT157 with metformin induced enhanced inhibition of p-IGF1R, p-ERK1/2 and p-mTOR. Moreover, we demonstrated that IRS1 functions as a critical mediator of the crosstalk between FGFR1 and IGF1R pathways, which involves a feedback loop between IRS1 and MAPK/ERK. Our study highlights the significance of FGFR1 status and IRS1 activation in metformin-resistance, which will facilitate the development of strategies targeting FGFR overexpression-associated metformin resistance.

SKP2 siRNA inhibits the degradation of P27kip1 and down-regulates the expression of MRP in HL-60/A cells.

S-phase kinase-associated protein 2 (SKP2) gene is a tumor suppressor gene, and is involved in the ubiquitin-mediated degradation of P27kip1. SKP2 and P27kip1 affect the proceeding and prognosis of leukemia through regulating the proliferation, apoptosis and differentiation of leukemia cells. In this study, we explored the mechanism of reversing of HL-60/A drug resistance through SKP2 down-regulation. HL-60/A cells were nucleofected by Amaxa Nucleofector System with SKP2 siRNA. The gene and protein expression levels of Skp2, P27kip1, and multi-drug resistance associated protein (MRP) were determined by reverse transcription-polymerase chain reaction and western blot analysis, respectively. The cell cycle was analyzed by flow cytometry. The 50% inhibitory concentration value was calculated using cytotoxic analysis according to the death rate of these two kinds of cells under different concentrations of chemotherapeutics to compare the sensitivity of the cells. HL-60/A cells showed multi-drug resistance phenotype characteristic by cross-resistance to adriamycin, daunorubicin, and arabinosylcytosine, due to the expression of MRP. We found that the expression of SKP2 was higher in HL-60/A cells than in HL-60 cells, but the expression of P27kip1 was lower. The expression of SKP2 in HL-60/A cells nucleofected by SKP2 siRNA was down-regulated whereas the protein level of P27kip1 was up-regulated. Compared with the MRP expression level in the control group (nucleofected by control siRNA), the mRNA and protein expression levels of MRP in HL-60/A cells nucleofected by SKP2 siRNA were lower, and the latter cells were more sensitive to adriamycin, daunorubicin, and arabinosylcytosine. Down-regulating the SKP2 expression and arresting cells in the G0/G1 phase improve drug sensitivity of leukemia cells with down-regulated MRP expression.

SENP2 suppresses NF-κB activation and sensitizes breast cancer cells to doxorubicin.

Doxorubicin is a chemotherapeutic agent commonly used to treat breast cancer. However, breast cancer often develops drug resistance, leading to disease recurrence and poor prognosis. Delineating the mechanisms underlying drug resistance is imperative for overcoming the challenge of treating doxorubicin-resistant breast cancer. In this study, by identifying the possible role of Sentrin/SUMO-specific proteases (SENPs) in doxorubicin resistance, we show here that among the 6 members of SENPs, only SENP2 is downregulated in doxorubicin-resistant MCF-7 (MCF-7/adr) and MDA-MB-231 (dr) breast cancer cells, as compared with sensitive counterparts. In addition, functionally, SENP2 overexpression resensitizes resistant breast cancer cells to doxorubicin treatment, and its knockdown confers doxorubicin resistance in sensitive ones. Moreover, NF-κB pathway is activated in MCF-7/adr cells, however, treatment with Bay 11-7085, one specific inhibitor of this pathway, reverses resistance to doxorubicin, suggesting that NF-κB pathway activation contributes to doxorubicin resistance in MCF-7/adr cells. We further show that SENP2 overexpression enhances NEMO deSUMOylation and suppresses NF-κB activation particularly in MCF-7/adr cells. Furthermore, SENP2 overexpression-induced sensitivity of MCF-7/adr cells to doxorubicin is drastically abrogated when treated with NF-κB pathway activator, thus establishing a causal link between SENP2-suppressed NF-κB pathway and enhanced doxorubicin sensitivity in breast cancer cells. Overall, this study reveals a novel function of SENP2 in counteracting doxorubicin resistance in breast cancer, and highlights the critical role of NF-κB suppression in mediating this effect.

Basic Fibroblast Growth Factor Protects Astrocytes Against Ischemia/Reperfusion Injury by Upregulating the Caveolin-1/VEGF Signaling Pathway.

A previous in vivo study demonstrated that intracerebroventricular injection of basic fibroblast growth factor (bFGF) in middle cerebral artery occlusion rats increased the expression of caveolin-1 (cav-1) and vascular endothelial growth factor (VEGF) in cerebral ischemia penumbra. Because astrocytes are the largest population in the brain, the aim of this in vitro study was to investigate the influence of bFGF on cav-1 and VEGF expression in rat astrocytes following oxygen glucose deprivation/reoxygenation (OGD/R). For this, an ischemic model in vitro of oxygen glucose deprivation lasting for 6 h, followed by 24 h of reoxygenation was used. Primary astrocytes from newborn rats were pre-treated with siRNA targeting bFGF before OGD/R. Cell viability was measured by a CCK-8 assay. The protein and mRNA expressions of bFGF, cav-1, and VEGF were evaluated by western blotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction. The results showed that OGD/R reduced cell viability, which was decreased further following bFGF knockdown; however, restoring bFGF improved cell survival. A cav-1 inhibitor abrogated the effect of bFGF on cell viability. The expression levels of bFGF mRNA, bFGF protein, cav-1 mRNA, cav-1 protein, and VEGF protein were higher in OGD/R astrocytes. bFGF knockdown markedly decreased the expression levels of cav-1 mRNA, cav-1 protein, and VEGF protein, which were effectively reversed by exogenous bFGF treatment. Moreover, exogenous bFGF treatment significantly increased the expression levels of cav-1 mRNA, cav-1 protein, and VEGF protein in OGD/R astrocytes; however, a cav-1 inhibitor abolished the effect of bFGF on VEGF protein expression. These results suggested that bFGF may protect astrocytes against ischemia/reperfusion injury by upregulating caveolin-1/VEGF signaling pathway.