901–85 Lp(a) is a Predictor of Coronary Artery Disease in Pre-menopausal but not in Post-menopausal Women

Coronary artery disease (CAD) risk increases in women after menopause. Although numerous reports suggest that lipid profile worsening after menopause may be associated with an increase in CAD among women, there have been few studies that discussed the contribution of Lp(a). To examine the association between CAD and Lp(a) in pre-menopausal (PR, <55 yo) and post-menopausal (PO, ≥55 yo) women, we evaluated Lp(a) levels and other risk factor prevalence in 180 female patients (20 to 77 yo) with angiographically defined CAD. Six risk factors were assessed: hyper-Lp(a)emia (Hi-Lp(a), Lp(a)≥30mg/dl). hyper-LDLemia (Hi-LDL, LDL≥160mg/dl). hypo-HDLemia (Lo-HDL, HDL<35mg/dl), hypertension, diabetes, and smoking. Cases were defined as those who had >1 coronary artery with >50% stenosis. There were more patients with Hi-Lp(a) (61%*vs 27%), Hi-LDL (61%**vs 5%) and smoking (61%**vs 9%) in PR cases (n=18) as compaved with those in PR controls (n=22). PO cases (n=93) had more Lo-HDL (15%*vs 2%), diabetes (33%**vs 13%) and smokers (61%**vs 9%) than PO controls (n=47) did. The median Lp(a) of PR cases was higher than that of PR controls (38.8*, 22.7mg/dl), and they increased with number of diseased arteries. In contrast, there was no difference in the Lp(a) levels between PO cases and PO controls (21.7, 25.2mg/dl). Logistic regression model also revealed that Hi-Lp(a) was an independent predictor of CAD after controlling for Hi-LDL, Lo-HDL, hypertension, diabetes and smoking among PR (B=2.44, SE=1.20, p<0.05), but not among PO. Our data suggests that Lp(a) may be a strong risk factor for CAD in pre-menopausal women, and in post-menopausal women other risk factors, such as an estrogen deficiency, may play an important role. (*p<0.05, **p<0.01)

Distance-d independent set problems for bipartite and chordal graphs

The paper studies a generalization of the INDEPENDENT SET problem (IS for short). A distance-d independent set for an integer d≥2 in an unweighted graph G=(V,E) is a subset S⊆V of vertices such that for any pair of vertices u,v∈S, the distance between u and v is at least d in G. Given an unweighted graph G and a positive integer k, the DISTANCE-d INDEPENDENT SET problem (D d IS for short) is to decide whether G contains a distance-d independent set S such that |S|≥k. D2IS is identical to the original IS. Thus D2IS is NP-complete even for planar graphs, but it is in P for bipartite graphs and chordal graphs. In this paper we investigate the computational complexity of D d IS, its maximization version MaxD d IS, and its parameterized version ParaD d IS(k), where the parameter is the size of the distance-d independent set: (1) We first prove that for any ε>0 and any fixed integer d≥3, it is NP-hard to approximate MaxD d IS to within a factor of n1/2−ε for bipartite graphs of n vertices, and for any fixed integer d≥3, ParaD d IS(k) is W[1]-hard for bipartite graphs. Then, (2) we prove that for every fixed integer d≥3, D d IS remains NP-complete even for planar bipartite graphs of maximum degree three. Furthermore, (3) we show that if the input graph is restricted to chordal graphs, then D d IS can be solved in polynomial time for any even d≥2, whereas D d IS is NP-complete for any odd d≥3. Also, we show the hardness of approximation of MaxD d IS and the W[1]-hardness of ParaD d IS(k) on chordal graphs for any odd d≥3

Dissolution-permeation of hot-melt extruded amorphous solid dispersion comprising an experimental grade of HPMCAS

Background and purpose: Physicochemical properties of an amorphous solid dispersion (ASD) comprising an experimental grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-MX) with lower glass transition temperature have been previously investigated. This study aimed to evaluate applicability of HPMCAS-MX to hot-melt extrusion (HME) and dissolution-permeation performance of prepared ASDs using MicroFLUX. Review approach: A physical mixture of indomethacin (IMC) and HPMCAS-MX or -MG (a commercial grade with higher transition temperature) at 20:80 weight ratio was hot-melt extruded to prepare an ASD (IMC-MX and IMC-MG, respectively). The dissolution-permeation performance and the stability of the ASDs were measured. Key results: A torque reduction at 120 °C implied that IMC-MX transformed into an amorphous state at this temperature, but IMC-MG required around 170 °C. This result was supported by Raman mapping of the the HME samples. IMC-MG and IMC-MX remained in an amorphous state at 40 °C for three months. The initial dissolution rate and solubility of the ASDs were higher than that of crystalline IMC. The apparent permeability of IMC from IMC-MX and IMC-MG was comparable but was approximately two-fold higher than that from crystalline IMC. Conclusion: HPMCAS-MX enabled HME process at a lower temperature and improved the dissolution-permeation performance of indomethacin

Short-hairpin RNAs synthesized by T7 phage polymerase do not induce interferon

RNA interference (RNAi) mediated by small-interfering RNAs (siRNAs) is a highly effective gene-silencing mechanism with great potential for gene-therapeutic applications. siRNA agents also exert non-target-related biological effects and toxicities, including immune-system stimulation. Specifically, siRNA synthesized from the T7 RNA polymerase system triggers a potent induction of type-I interferon (IFN) in a variety of cells. Single-stranded RNA also stimulates innate cytokine responses in mammals. We found that pppGn (n = 2,3) associated with the 5′-end of the short-hairpin RNA (shRNA) from the T7 RNA polymerase system did not induce detectable amounts of IFN. The residual amount of guanine associated with the 5′-end and hairpin structures of the transcript was proportional to the reduction of the IFN response. Here we describe a T7 pppGn (n = 2,3) shRNA synthesis that does not induce the IFN response, and maintains the full efficacy of siRNA

Suppression of Hepatitis C Virus Core Protein by Short Hairpin RNA Expression Vectors in the Core Protein Expression HUH-7 Cells

Short hairpin RNAs (shRNAs) efficiently inhibit gene expression by RNA interference. Here, we report the efficient inhibition by DNA-based vector-derived shRNAs of core protein expression in Huh-7 cells. The shRNAs were designed to target the core region of the hepatitis C virus (HCV) genome. The core region is the most conserved region in the HCV genome, making it an ideal target for shRNAs. We identified an effective site on the core region for suppression of the HCV core protein. The HCV core protein in core protein-expressing Huh-7 cells was downregulated by core protein-shRNA expression vectors (core-shRNA-452, 479, and 503). Our results support the feasibility of using shRNA-based gene therapy to inhibit HCV core protein production