Bavachin Rejuvenates Sensitivity of Colistin against Colistin-Resistant Gram-Negative Bacteria.

The emergence of plasmid-mediated colistin resistance threatens the efficacy of colistin as a last-resort antibiotic used to treat infection caused by Gram-negative bacteria (GNB). Given the shortage of new antibiotics, the discovery of adjuvants to existing antibiotics is a promising strategy to combat infections caused by multidrug-resistant (MDR) GNB. This study was designed to investigate the potential synergistic antibacterial activity of bavachin, a bioactive compound extracted from the Psoralea Fructus, combined with colistin against MDR GNB. Herein, the synergistic efficacy in vitro and the therapeutic efficacy of colistin combined with bavachin in vivo were evaluated. The synergistic mechanism was detected by fluorescent probe and the transcript levels of mcr-1. Bavachin combined with colistin showed an excellent synergistic activity against GNB, as the FICI ≤ 0.5. In contrast to colistin alone, combination therapy dramatically increased the survival rate of Galleria mellonella and mice in vivo. Moreover, the combination of bavachin and colistin significantly reduced the amount of bacterial biofilm formation, improved the membrane disruption of colistin and inhibited mcr-1 transcription. These findings show that bavachin is a potential adjuvant of colistin, which may provide a new strategy to combat colistin-resistant bacteria infection with lower doses of colistin.

Isopropoxy Benzene Guanidine Ameliorates Streptococcus suis Infection In Vivo and In Vitro.

Streptococcus suis, an encapsulated zoonotic pathogen, has been reported to cause a variety of infectious diseases, such as meningitis and streptococcal-toxic-shock-like syndrome. Increasing antimicrobial resistance has triggered the need for new treatments. In the present study, we found that isopropoxy benzene guanidine (IBG) significantly attenuated the effects caused by S. suis infection, in vivo and in vitro, by killing S. suis and reducing S. suis pathogenicity. Further studies showed that IBG disrupted the integrity of S. suis cell membranes and increased the permeability of S. suis cell membranes, leading to an imbalance in proton motive force and the accumulation of intracellular ATP. Meanwhile, IBG antagonized the hemolysis activity of suilysin and decreased the expression of Sly gene. In vivo, IBG improved the viability of S. suis SS3-infected mice by reducing tissue bacterial load. In conclusion, IBG is a promising compound for the treatment of S. suis infections, given its antibacterial and anti-hemolysis activity.

Prognosis in different subtypes of metaplastic breast cancer: a population-based analysis.

BACKGROUND: Metaplastic breast cancer (MpBC) is a rare histological subtype of breast cancer recognized as a unique pathologic entity in 2000. However, the pathogenesis, optimal therapy, and prognosis of MpBC and the potential effect of systemic treatments on different subtypes of MpBC are not well defined. METHODS: A retrospective population-based study was performed to identify breast cancer patients with MpBC and other triple-negative breast cancers (TNBC) between 2010 and 2014 using the surveillance, Epidemiology, and End Results (SEER) database. Chi-square test was used to analyze characteristics between subgroups. Kaplan-Meier analysis and Multivariate Cox regressions were used to evaluate overall survival (OS) of MpBC, TNBC, and MpBC subgroups. Competing risk analysis and multivariate regression model of competing risk were used to assess breast cancer-specific survival (BCSS) of MpBC and TNBC RESULTS: We identified a study cohort of 22,433 patients (1112 MpBC and 21,321 TNBC). MpBC correlated with older population, larger tumor size and less lymph node involvement, and TNBC phenotype. Patients with MpBC especially with triple-negative subtype (TN-MpBC) had worse survival than the overall TNBC population. However, the prognosis of MpBC without triple-negative subtype (non-TN MpBC) was not different from that of TNBC. In Kaplan-Meier analysis, chemotherapy was not associated with significant difference in OS of TN-MpBC. In non-TN MpBC group, the 3-year OS was 79.8% for patients receiving chemotherapy and 70.5% in patients without chemotherapy, and chemotherapy was associated (P = 0.033) with improved OS. Within the MpBC patients, radiotherapy was significantly (HR 1.544; 95% CI 1.148-2.078; P = 0.004) associated with improved OS and (HR 1.474; 95% CI 1.067-2.040; P = 0.019) BCSS. CONCLUSIONS: Patients with TN-MpBC had worse prognosis than TNBC and chemotherapy was not associated with improved survival. In contrast, non-TN MpBC may derive survival benefit from chemotherapy and radiotherapy.

Inulin-like polysaccharide ABWW may impede CCl4 induced hepatic stellate cell activation through mediating the FAK/PI3K/AKT signaling pathway in vitro & in vivo.

Studies have shown that terrestrial acidic polysaccharides containing carboxyl groups and seaweed sulfated polysaccharides have strong potential in anti-liver fibrosis. However, there is no investigation on the anti-liver fibrosis of fructan, a ubiquitous natural polysaccharide. The present study aimed to understand the effect of fructan in ameliorating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Here, an inulin-like fructan ABWW from Achyranthes bidentata Bl. was characterized by fructose enzymatic hydrolysis, methylation analysis, ESI-MS, and NMR. It was composed of →2)-ß-d-Fruf-(1→ and →2)-ß-d-Fruf-(1, 6→, terminated with →1)-α-d-Glcp and →2)-ß-d-Fruf residues. The biological studies showed that ABWW could improve liver damage and liver fibrosis induced by CCl4in vivo and inhibit hepatic stellate cell (HSC) activation and migration in vitro. We further demonstrated that ABWW inhibited LX2 activation via suppressing the FAK/PI3K/AKT signaling pathway. Hence, ABWW might be a potential novel active compound for anti-fibrosis new drug development.

Nine-Year Median Follow-up of Cardiotoxicity and Efficacy of Trastuzumab Concurrently With Anthracycline-Based and Anthracycline-Free Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer Patients.

BACKGROUND: The combination of trastuzumab with anthracycline chemotherapy drugs is associated with synergistic cardiotoxicity. The aim of this study is to compare the efficacy and late-onset cardiac toxicity of neoadjuvant chemotherapy regimens, trastuzumab plus paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (PH-FECH) versus trastuzumab plus docetaxel and carboplatin (TCH), for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). METHODS: Patients with HER2+ BC who received neoadjuvant chemotherapy with PH-FECH or TCH between 2002 and 2009 at MD Anderson Cancer Center were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints included pathological complete response (pCR), overall survival, cardiac events, breast cancer-specific survival, noncardiac toxicities, and chemotherapy interruption. RESULTS: We identified 249 consecutive patients (184 who received PH-FECH and 65 who received TCH). The 10-year PFS was higher in the PH-FECH group than in the TCH group (83.6% vs. 72.2%; P = .044). The pCR rate was significantly higher in the PH-FECH group (58.2% vs. 41.5%; P = .021). The rate of cardiac events was higher in the PH-FECH group, but the difference was not significant (13.0% vs. 7.7%; P = .352). More patients developed late-onset cardiotoxicity in the PH-FECH group (3.8%) than in the TCH group (1.5%). Hypertension (odds ratio, 4.402 [95% confidence interval, 1.020-18.998]; P = .047) was an independent predictor of late-onset cardiotoxicity. CONCLUSIONS: Both neoadjuvant regimens are effective and tolerable in patients with HER2+ BC. The PH-FECH regimen offers a higher pCR rate and higher PFS but no difference in overall survival or breast cancer-specific survival. Higher frequency of cardiac toxicity with PH-FECH was noted.

Association of Cardiovascular Disease Risk Factors with Late Cardiotoxicity and Survival in HER2-positive Breast Cancer Survivors.

PURPOSE: Breast cancer and cardiovascular (CV) diseases often share the same risk factors. It is increasingly important to identify risk factors for CV events in patients with high-risk breast cancer and explore optimal treatment regimens. EXPERIMENTAL DESIGN: Early HER2-positive breast cancer patients at our institution between January 1998 and October 2009 were reviewed. Primary outcome was late-severe-CV-event-free survival, and late severe CV events were defined as cardiovascular death, cardiomyopathy, symptomatic heart failure, and myocardial infarction developing 2+ years after breast cancer diagnosis. Kaplan-Meier plots, Cox proportional hazard regressions, and restricted mean survival time were used to evaluate outcomes. RESULTS: We identified 2,448 consecutive eligible patients with a median follow-up time of 111.0 months (interquartile range, 52.0-151.8 months). One hundred and thirty-six patients had late severe CV events and 752 died of any cause [533 (70.9%) died of primary breast cancer; 12 (1.6%) died of cardiovascular disease]. Hypertension [HR, 1.546; 95% confidence interval (95% CI), 1.030-2.320; P = 0.036] and history of coronary artery disease (CAD; HR, 3.333; 95% CI, 1.669-6.656; P < 0.001) were associated with worse late-severe-CV-event-free survival. Anthracycline-containing regimens (HR, 1.536; 95% CI, 0.979-2.411; P = 0.062) was not a significant risk factor for CV events in multivariate analysis. Regimens containing both anthracycline and anti-HER2 therapy were prognostic for better OS (HR, 0.515; 95% CI, 0.412-0.643; P < 0.001). CONCLUSIONS: Hypertension and CAD history were independent prognostic factors for late severe CV events. Adding anti-HER2 agents to anthracycline-containing regimens did not substantially increase the risk for late severe cardiotoxicity and conferred better overall survival.

Prognosis of ovarian clear cell cancer compared with other epithelial cancer types: A population-based analysis.

In order to compare the clinicopathological characteristics and survival outcomes of patients with ovarian clear cell carcinoma (CCC) to other epithelial cancer types, a total of 27,290 patients were analyzed, including 2,424 patients with CCC (8.9%), 3,505 patients with endometrioid cancer (EC) (12.8%), 2,379 patients with mucinous cancer (MC) (8.7%) and 18,982 patients with serous cancer (SC) (69.6%). Patients with EC had the most favorable prognosis and patients with SC had the poorest prognosis among all epithelial ovarian cancers. Among patients with stage I cancer, patients with CCC had a more favorable prognosis compared with patients with SC, especially after 60 months (landmark analysis results, HR=2.079, P=0.001) and had a poorer prognosis compared with patients with MC [restricted mean survival time (RMST) difference, -3.434 months]. Among patients at stages III and IV, patients with CCC had a poorer prognosis compared with patients with SC (RMST difference in stage III, -7.588 months; RMST difference in stage IV, -15.445 months) and had a more favorable prognosis compared with patients with MC (RMST difference in stage III, 10.850 months; RMST difference in stage IV, 8.430 months). The present results suggested that most patients with CCC exhibited, high grade, an early stage, unilateral status and were of a young age. In general, patients with SC presented the poorest prognosis among all patients with epithelial ovarian cancer and no significant survival difference was found between patients with CCC and MC. However, after adjusting for stage using pairwise comparisons, the prognosis of patients with CCC was found to be more favorable compared with the patients with SC and worse compared with patients with MC at stage I; the results at stage III-IV were opposite and the prognosis of patients with CCC was worse compared with the patients with SC and more favorable compared with the patients with MC.

The role of long non-coding RNA GAS5 in cancers.

Long non-coding RNAs (lncRNAs) have shown potential as a biomarker in the diagnosis and prognosis in multiple cancers. LncRNAs are dysregulated in various cancers, playing either oncogenic or tumor suppressive roles. Emerging evidences have proved that the growth arrest-specific 5 (GAS5) lncRNA can function as a tumor suppressor in several cancers. LncRNA GAS5 is downregulated in many types of cancer, regulating cellular processes such as cell proliferation, apoptosis and invasion. The low level of GAS5 expression often elevates capacity of proliferation and predicts poorer prognosis in some cancers. This review aims to summarize the recent published literature on the biogenesis, regulation mechanism and function of GAS5 in different types of cancers and explore its potential for cancer diagnosis, prognosis and treatment.