BackgroundInvasive micropapillary carcinoma (IMPC) of the breast is a rare subtype of breast cancer that is associated with a high incidence of regional lymph node metastases and a poor clinical outcome. However, the clinico-pathological features and prognostic factors of IMPC are not well understood.Patients and MethodsA total of 188 IMPC cases and 1,289 invasive ductal carcinoma (IDC) cases were included. The clinical features, breast cancer-specific survival (BCSS) and recurrence/metastasis-free survival (RFS) of the patients were compared between these two groups.ResultsThe IMPC patients exhibited more features of aggressive carcinoma than the IDC patients, including larger tumor size, higher tumor stage, a greater proportion of nodal involvement and an increased incidence of lymphovascular invasion. Patients with IMPC had lower 5-year BCSS and RFS rates (75.9% and 67.1%, respectively) than patients with IDC (89.5% and 84.5%, respectively). Compared to IDC patients, the patients with IMPC had a significantly higher percentage of stage III breast cancer (51.3% versus 21.7%). In a stage-matched Kaplan-Meier analysis, the patients with stage III IMPC had lower 5-year BCSS and RFS rates than patients with stage III IDC (BCSS, P = 0.004; RFS, P = 0.034). A multivariate analysis revealed that TNM stage was an independent prognostic factor for patients with IMPC. The proportion of cancers with a luminal-like subtype was significantly higher in IMPC than in IDC (P<0.001). However, after matching by molecular subtype, the patients with IMPC had significantly worse clinical outcomes than patients with IDC.ConclusionsIn Chinese women, IMPCs displayed more aggressive behaviors than IDCs, resulting in poorer clinical outcomes for patients with IMPC, regardless of a favorable molecular subtype. Our findings illustrate that the poorer survival of patients with IMPC might be due to an increased incidence and aggressiveness of tumors in TNM stage III.

Poly(amido amine) (PAMAM) dendrimers are promising nanocarriers in a wide range of biomedical applications including gene and drug delivery and as imaging agents. They have unique structural properties and are characterized by high size uniformity, low polydispersity, and a large number of modifiable surface groups. Drug-dendrimer systems are usually further modified through the conjugation of ligands in order to confer the carriers' specific characteristics designed to enhance their efficacy. The chemistry and structure of the solvated ligand-conjugated dendrimer nanocarriers (DNCs) will dictate how they interact with the physiological environment and, therefore, their fate and function. Understanding the microstructures of ligand-conjugated DNCs is, therefore, of great relevance within the context of drug delivery applications. In this work, we investigate the effect of poly(ethylene glycol) (PEG) on the microstructure of solvated, NH2-terminated PAMAM DNCs using fully atomistic molecular dynamics simulations. Several variables including dendrimer generation (2-5), PEGylation density (0-50%), and PEG Mw (500 and 1000) were investigated. The results obtained showed a good match with available experimental results, including size as a function of dendrimer degeneration (G2NH2-G5NH2). No back-folding is observed for PAMAM dendrimers with generation lower than G5NH2. G2NH2 and G3NH2 showed a dense-packed, nonglobular structure, and G4NH2 and G5NH2 have a segmented, "open" structure. Our results help settle a long-standing debate with respect to "back-folding" as the microstructural information obtained here is reconciled with experimental results. PEGylation was found to influence the microstructure in a different way, including an expected increase in the overall size of the DNCs, while not affecting much the solvation of unmodified terminal (primary) amines. It also serves to expand the core of dendrimers, reduce the surface charge, and change solvation behavior of different generation branching amines. We show that the microstructure of a PEG layer with the same number of repeat units can be significantly altered by changing the grafting density and size of PEG. Potential consequences in the design of PEGylated dendrimers for drug delivery and targeting are discussed based on the obtained microstructural information.

Background:Probiotics supplements provide a new nonpharmacological alternative to reduce cardiovascular risk factors. The impact of probiotics on the reduction of total cholesterol (TC) remains controversial. We conducted a meta-analysis to showcase the most updated and comprehensive evaluation of the studies.Methods:Randomized controlled trials (RCTs) were searched from electronic databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang database dating from January 2007 to January 2017. The curative effects of probiotics on the reduction of TC were assessed using mean difference (MD), as well as their 95% confidence interval (CI). RevMan software (version 5.3) was used to carry out this meta-analysis.Results:Thirty-two RCTs including 1971 patients met the inclusion criteria. Results of this analysis showed that compared with the control group serum TC was significantly reduced in probiotics group [MD = −13.27, 95% CI (−16.74 to 9.80), P < .05]. In addition, specific strains also significantly reduced serum TC, L acidophilus and B lactis [MD = −8.30, 95% CI (−10.44, −6.15), P < .05]; VSL#3 [MD = −11.04, 95% CI (−19.61, −2.48), P < .05]; L plantarum t ≤ 6 weeks: [MD = −1.56, 95% CI (−6.97, −3.86), P < .05] or t > 6 weeks: [MD = −22.18, 95% CI (−28.73, −15.63), P < .05]. Subgroup analysis indicated that the difference of baseline TC, probiotics forms and intervention duration might have a significant impact on the results. However, strains and doses of probiotics had no significant influence on curative effects.Conclusion:Available evidence indicates that probiotics supplements can significantly reduce serum TC. Furthermore, higher baseline TC, longer intervention time, and probiotics in capsules form might contribute to a better curative effect.

Bile salts are endogenous surfactants which have been widely used in drug formulation and drug delivery systems to increase drug permeation. When given by subcutaneous injection to rats, the novel bile salt, monoketocholate (MKC) has been shown to increase brain uptake of several drugs. This study aimed to characterize the physicochemical and some biological properties of MKC as a basis for understanding the mechanism by which it enhances membrane permeability. Comparison was made with three natural bile salts, cholate, deoxycholate and taurocholate. Critical micelle concentrations (CMC) were measured by the surface tension method and partition coefficients in n-octanol/buffer were measured by liquid-liquid extraction. The effects of bile salts on three different biological membrane models were investigated. Penetration studies in Langmuir monolayers indicated that MKC has only a weak ability to insert into phospholipid monolayers, but it can increase their elasticity once incorporated. In the erythrocyte model, MKC did not cause hemolysis at concentrations up to 10 mM, but changed the deformability of erythrocytes. Studies of the permeability of mannitol and transepithelial electrical resistance (TEER) across Caco-2 cell monolayers showed MKC did not cause significant increases in mannitol permeability or decreases in TEER values. In conclusion, MKC does not display strong membrane-solubilizing properties, but does change the mechanical properties of biological membranes. This effect might influence both passive and active transcellular permeation.

1. The aim of the present study was to perform an in vivo estimation of the Michaelis-Menten constants of the major metabolic pathways of paracetamol (APAP). 2. A two-occasion, single-dose cross-over trial was performed using 60 and 90 mg/kg doses of APAP in healthy patients undergoing third molar dental extraction. Plasma samples were collected over 24 h and urine was collected for 8 h after dosing. Twenty patients were enrolled in the study and complete data for plasma and urine were available for both doses for 13 volunteers who were included in the analysis; seven of the volunteers were men, the median age (range) was 22 years (19-31) and the median weight (range) was 68 kg (50-86). 3. The mean (95% CI) k(m) for APAP glucuronidation was 6.89 mmol/L (3.57-10.22) and the V(max) was 0.97 mmol/h per kg (0.65-1.28). The k(m) for APAP sulphation was 0.097 mmol/L (0.041-0.152) and the V(max) was 0.011 mmol/h per kg (0.009-0.013). For the combined excretion of APAP-cysteine and APAP-mercapturate, the k(m) was 0.303 mmol/L (0.131-0.475) and the V(max) was 0.004 mmol/h per kg (0.002-0.005). 4. The estimates for in vivo Michaelis-Menten constants for APAP glucuronidation and sulphation were in the order of those reported previously using in vitro methods.