Treatment efficacy of tigecycline in comparison to cefoperazone/ sulbactam alone or in combination therapy for carbapenenm-resistant Acinetobacter baumannii infections.

Tigecycline (TGC) and cefoperazone/sulbactam (CPS) both have been shown good in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAB) isolates. We aim to compare the efficacy of TGC versus CPS for CRAB infections. We conducted a retrospective cohort study of patients with CRAB at a single center in China from 2013 to 2015. Outcomes comprised in-hospital mortality, clinical and microbiological response. The method of inverse probability of treatment weighting and multivariable logistic regression analysis incorporated with propensity score were employed to estimate the effect of treatment groups. There were 130 subjects included in our study. The patients in TGC, CPS and TGC plus CPS combination group were 42, 66, and 22, respectively. After adjustment, in-hospital mortality was lower in CPS group than TGC group (weighted OR 0.173; 95% CI 0.06-0.497; P=0.001) but without differences in clinical success and microbiological eradication (P>0.05). TGC monotherapy had a similar outcome with TGC plus CPS combination group. This is the first study comparing the efficacy of tigecycline and cefoperazone/sulbactam for CRAB infections. Cefoperazone/sulbactam appears to be more efficacious than tigecycline during treatment.

Transgelin 2 Promotes Paclitaxel Resistance, Migration, and Invasion of Breast Cancer by Directly Interacting with PTEN and Activating PI3K/Akt/GSK-3ß Pathway.

MDR and tumor migration and invasion are still the main obstacles to effective breast cancer chemotherapies. Transgelin 2 has recently been shown to induce drug resistance, tumor migration, and invasion. The aim of this study was to determine the biological functions of Transgelin 2 and the mechanism underlying how Transgelin 2 induces paclitaxel (PTX) resistance and the migration and invasion of breast cancer. We detected that the protein level of Transgelin 2 was significantly upregulated in breast cancer tissues compared with adjacent nontumor tissues. A bioinformatics analysis indicated that Transgelin 2 was significantly related to clinicopathologic parameters and patient prognosis. Overexpression of Transgelin 2 enhanced the migration and invasion of human breast cancer cells and decreased the sensitivity of breast cancer cells to paclitaxel. Meanwhile, the tumorigenesis and metastasis of breast cancer cells were also enhanced by Transgelin 2 overexpression in vivo Moreover, Transgelin 2 overexpression activated the PI3K/Akt/GSK-3ß pathway by increasing the phosphorylation levels of Akt and GSK-3ß and decreasing the expression of PTEN. We also found that Transgelin 2 could directly interact with PTEN and was located upstream of PTEN. Furthermore, the PI3K/Akt pathway inhibitor MK-2206 reversed the resistance to paclitaxel and inhibited the migration and invasion of breast cancer cells. These findings indicate that Transgelin 2 promotes paclitaxel resistance and the migration and invasion of breast cancer by directly interacting with PTEN and activating the PI3K/Akt/GSK-3ß pathway. Transgelin 2 may therefore be useful as a novel biomarker and therapeutic target for breast cancer.

Network meta-analysis and pharmacoeconomic evaluation of antibiotics for the treatment of patients infected with complicated skin and soft structure infection and hospital-acquired or ventilator-associated penumonia.

Background: Infections due to methicillin-resistant Staphylococcus aureus (MRSA) cause serious health risks and significant economic burdens and the preferred drugs are still controversial. Methods: We performed a network meta-analysis (NMA) to compare the efficacy and safety of antibiotics used to treat inpatients with complicated skin and soft structure infections (cSSSI) or hospital-acquired or ventilator-associated pneumonia (HAP/VAP). We also developed a decision tree model to assess the cost-effectiveness of antibiotics. Results: Forty-nine randomized controlled trials met the inclusion criteria (34 for cSSSI, 15 for HAP/VAP) and compared the efficacy and safety of 16 antibiotics. For cSSSI, NMA indicated that for clinical cure, linezolid was superior than vancomycin (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.19-2.02), while tedizolid (OR 1.39, CI 0.70-2.76) was similar to vancomycin. In terms of safety, there were no significant differences between any two interventions on total adverse events. Based on drug and hospital costs in America, the incremental cost-effectiveness ratios (ICERs) per life-year saved for linezolid and tedizolid compared with vancomycin were US$2833 and US$5523. For HAP/VAP, there were no significant effects either for clinical cure or for safety endpoints between linezolid and vancomycin in NMA. ICERs per life-year saved for linezolid compared with vancomycin were US$2185. Conclusion: In these clinical trials, considering efficacy, safety, and cost-effectivenes, linezolid and tedizolid showed their superiority in MRSA cSSSI; while linezolid might be recommended to treat MRSA pneumonia. Although vancomycin was not cost-effective in pharmacoeconomic evaluation, it is still the first-line treatment for MRSA infection in the clinical practice. This study might provide new insights of therapeutic choices for patients with MRSA infections whilst awaiting the arrival of higher quality evidence.

Transgelin-2 expression in breast cancer and its relationships with clinicopathological features and patient outcome.

BACKGROUND: Transgelin-2 is an actin-binding protein that is widely expressed in various tissues and organs of the body, and reportedly may participate in the development and progression of multiple cancers. However, the clinical significance of transgelin-2 still remains controversial. We, therefore, aimed to determine the expression of transgelin-2 in breast cancer as well as its correlation with the tumorigenesis, progression and prognosis of human breast cancer. METHODS: We collected tissues of 58 breast cancer patients from our hospital and 1090 samples from The Cancer Genome Atlas (TCGA) database. X-tile software was used to divide the transgelin-2 mRNA expression level in the database, logistic regression model was used to identify independent factors influencing transgelin-2 mRNA expression, and then Cox regression and Kaplan-Meier analysis were used to find factors that influence survival of breast cancer. RESULTS: Transgelin-2 was significantly overexpressed in breast cancer tissues from our hospital and receiver operating characteristic (ROC) curve indicated that transgelin-2 may have diagnostic value. Meanwhile, estrogen receptor (ER) was in inverse correlation with transgelin-2 protein and mRNA expression, and transgelin-2 expression was positively correlated with Ki67 in breast cancer tissues. Logistic regression model revealed that TNM stage, ER and progesterone receptor (PR) status were independent factors for transgelin-2 mRNA expression. Patients with high transgelin-2 mRNA expression showed a poor survival and the trend was statistically significant only in ER-negative patients. CONCLUSIONS: Transgelin-2 was expressed significantly higher in breast cancer cells and correlated with some clinicopathological factors. High transgelin-2 expression might predict poor prognosis for ER-negative patients.

SE translation mRNA overexpression: a potential prognostic predictor in breast cancer.

BACKGROUND: Patient SE translation (SET) belongs to histone chaperone nucleosome assembly protein family and has been confirmed that it is associated with carcinogenesis, tumor progression and patient outcome. In this study, we aim at assessing the prognostic value of SET mRNA, the function and pathway of SET and its related genes in breast cancer. METHODS: The clinicopathological and prognostic significance of SET was assessed by the molecular taxonomy of breast cancer international consortium (METABRIC) database (n=1,904). Additionally, based on the data and network of SET and its related genes from cBioPortal website, their function in the progression of breast cancer was also explored. RESULTS: SET mRNA overexpression was a significant predictor of a poor prognosis (P=0.0006). The two signaling pathways associated with SET were the facilitating function of condensin II on mitosis and the accelerated transportation of tumor cell mRNA towards the extranuclear position, and SET acted to suppress condensin II and stabilize mRNA. CONCLUSIONS: Owing to the regulation of chromosome condensation and stabilization of tumor cell mRNA, overexpression of SET is correlated with aggressive phenotypes and facilitates tumor proliferation and deterioration. SET may act as a valuable prognosis biomarker in breast cancer.

Poor prognosis of nucleophosmin overexpression in solid tumors: a meta-analysis.

BACKGROUND: Nucleophosmin is a non-ribosomal nucleolar phosphoprotein that is found primarily in the nucleolus region of cell nucleus, plays multiple important roles in tumor processes. Accumulated previous studies have reported a potential value of NPM acted as a biomarker for prognosis in various solid tumors, but the results were more inconsistency. We performed this meta-analysis to precisely evaluate the prognostic significance of NPM in solid tumors. METHODS: Clinical data were collected from a comprehensive literature search in PubMed, Web of Science, Embase, and China National Knowledge Infrastructure databases (up to October, 2017). A total of 11 studied with 997 patients were used to assess the association of NPM expression and patients' overall survival (OS). The hazard ratio (HR) or odds ratio (OR) with its 95% confidence intervals (CI) were calculated to estimate the effect. RESULTS: The pooled results indicated that higher expression of NPM was observably correlated with poor OS in solid tumor (HR = 1.85, 95% CI: 1.44-2.38, P < 0.001). Furthermore, high expression of NPM was associated with some phenotypes of tumor aggressiveness, such as tumor stage (4 studies, III/IV vs. I/II, OR = 5.21, 95% CI: 2.72-9.56, P < 0.001), differentiation grade (poor vs. well/moderate, OR = 1.82, 95% CI: 1.01-3.27, P = 0.046). CONCLUSION: This meta-analysis indicated that NPM may act as a valuable prognosis biomarker and a potential therapeutic target in human solid tumors.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis.

BACKGROUND: Posaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs). METHODS: Bibliographic databases were searched (from inception to September 2017) to select studies including the clinical outcomes below and above concentration cut-off value of 0.5 mg/L and 0.7 mg/L. The reliability of the results were evaluated with trial sequential analysis (TSA). RESULTS: Twenty-eight studies with 1930 patients included were analyzed. The results of our pooled analysis demonstrated that patients with posaconazole plasma concentrations over 0.5 mg/L were twice more likely to achieve successful responses compared with those with lower concentrations (odds ratio, OR = 1.98, 95% confidence interval, CI 1.09-3.58, P = 0.02) while the threshold, 0.7 mg/L showed no significant difference (OR = 1.84, 95% CI 0.94-3.63, P = 0.08). The TSA results showed that there was sufficient information to support these findings. CONCLUSIONS: An optimal posaconazole concentration target of 0.5 mg/L is suggested to ensure the clinical prophylactic efficacy and may help reduce the dosage and dose-dependent toxicity comparing with the target of 0.7 mg/L.

Transgelin-2: A potential oncogenic factor.

Actin-binding proteins are proteins that could bind to actin or actin fibers. As a member of actin-binding proteins, Transgelin-2 is expressed in smooth muscle cells and non-smooth muscle cells, and its gene, TAGLN2, is differently expressed in all cells and tissues. The deregulation of Transgelin-2 is considered to be correlated with progression of many kinds of diseases, especially the development of malignant tumors, such as invasion, metastasis, and resistance, yet the function and mechanism of action of Transgelin-2 remain elusive. Therefore, we reviewed the basic characteristics and function of Transgelin-2 and its biological role in various types of diseases in order to provide the theoretical basis for further research and new perspectives on cancer development.

Metabolic profiling reveals altered pattern of central metabolism in navel orange plants as a result of boron deficiency.

We focused on the changes of metabolite profiles in navel orange plants under long-term boron (B) deficiency using a gas chromatography-mass spectrometry (GC-MS) approach. Curling of the leaves and leaf chlorosis were observed only in the upper leaves (present before start of the treatment) of B-deficient plants, while the lower leaves (grown during treatment) did not show any visible symptoms. The metabolites with up-accumulation in B-deficient leaves were mainly proline, l-ornithine, lysine, glucoheptonic acid, fucose, fumarate, oxalate, quinate, myo-inositol and allo-inositol, while the metabolites with down-accumulation in B-deficient leaves were mainly serine, asparagine, saccharic acid, citrate, succinate, shikimate and phytol. The levels of glucose and fructose were increased only in the upper leaves by B deficiency, while starch content was increased in all the leaves and in roots. The increased levels of malate, ribitol, gluconic acid and glyceric acid occurred only in the lower leaves of B-deficient plants. The increased levels of phenols only in the upper leaves indicated that the effects of B on phenol metabolism in citrus plants may be a consequence of disruptions in leaf structure. Metabolites with opposite reactions in upper and lower leaves were mainly glutamine, glycine and pyrrole-2-carboxylic acid. To our knowledge, the phenomena of allo-inositol even higher than myo-inositol occurred characterized for the first time in this species. These results suggested that the altered pattern of central metabolism may be either specific or adaptive responses of navel orange plants to B deficiency.