Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol).

PURPOSE: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol). EXPERIMENTAL DESIGN: ABI-007 and Taxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m(2), 30 minutes; n = 14) or Taxol (175 mg/m(2), 3 hours; n = 13), with cycles repeated every 3 weeks. RESULTS: The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m(2) (P = 0.048) and 663.8 versus 433.4 L/m(2) (P = 0.040), respectively]. CONCLUSIONS: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.     

Effects of active compounds from Cassia fistula on quorum sensing mediated virulence and biofilm formation in Pseudomonas aeruginosa

Pseudomonas aeruginosa infections are attributed to its ability to form biofilms and are difficult to eliminate with antibiotic treatment. Biofilm formation is regulated by quorum sensing (QS), an intracellular bacterial communication mechanism that allows the activation of numerous virulence factors and secondary metabolites. Targeting the QS pathway is a potential approach that prevents QS-controlled phenotypes and biofilm formation. For the first time, the current work has identified antiquorum sensing activity in the partially purified four fractions from the hot ethyl acetate extract of Cassia fistula fruit pods. Of the four fractions, only fraction-1 gave decreased AHL activity; the phytoconstituents in this fraction were identified as rhein, 3-aminodibenzofuran, 5-(hydroxymethyl)-2-(dimethoxymethyl)furan, and dihydrorhodamine. Fraction-1 (1 mg ml⁻¹) and rhein (0.15 mg ml⁻¹) showed 63% and 42.7% reduction in short-chain AHL production, respectively, without hindering the bacterial growth. Fraction-1 inhibited QS-mediated extracellular virulence factors viz. protease, elastase, pyocyanin, and rhamnolipid (p < 0.05). Quantitative analysis of biofilm formation showed 77% & 62.4% reduction by fraction-1 (1 mg ml⁻¹) and rhein (0.15 mg ml⁻¹) respectively. Confocal laser microscopy (CLMS) & scanning electron microscopy (SEM) confirmed the reduction of biofilm formation in Pseudomonas aeruginosa upon treatment with fraction-1 and rhein. Moreover, the in vivo study displayed that fraction-1 and rhein (standard) significantly enhanced the survival of Caenorhabditis elegans by suppressing the potency of virulence factors of Pseudomonas aeruginosa. Quantitative real-time polymerase chain reaction results demonstrated the down-regulation of QS-related genes, lasI, lasR, rhlI, and rhlR. In addition, in silico analysis divulged that a component identified by GC-MS displayed a strong affinity towards LasI and LasR. These findings suggest that potent phytochemicals from fraction-1, including rhein, could serve as novel phytotherapeutics in controlling emerging infections of antibiotic-resistant bacterial pathogens like Pseudomonas aeruginosa.

Pseudomonas aeruginosa infections are attributed to its ability to form biofilms and are difficult to eliminate with antibiotic treatment.     

Attitudes towards HPV testing: a qualitative study of beliefs among Indian,Pakistani, African-Caribbean and white British women in the UK

This study examined attitudes to human papillomavirus (HPV) testing among a purposively selected sample of women from four ethnic groups: white British, African Caribbean, Pakistani and Indian. The design was qualitative, using focus group discussion to elicit women's attitudes towards HPV testing in the context of cervical cancer prevention. The findings indicate that although some women welcomed the possible introduction of HPV testing, they were not fully aware of the sexually transmitted nature of cervical cancer and expressed anxiety, confusion and stigma about HPV as a sexually transmitted infection. The term 'wart virus', often used by medical professionals to describe high-risk HPV to women, appeared to exacerbate stigma and confusion. Testing positive for HPV raised concerns about women's sexual relationships in terms of trust, fidelity, blame and protection, particularly for women in long-term monogamous relationships. Participation in HPV testing also had the potential to communicate messages of distrust, infidelity and promiscuity to women's partners, family and community. Concern about the current lack of available information about HPV was clearly expressed and public education about HPV was seen as necessary for the whole community, not only women. The management of HPV within cervical screening raises important questions about informed participation. Our findings suggest that HPV testing has the potential to cause psychosocial harm to women and their partners and families.     

Liposarcoma of the breast--a case report

Sarcoma of the breast constitutes less than 1% of all malignant breast tumors and liposarcoma of the breast has an incidence of 0.3% of all the mammary sarcomas. A 90-year-old woman presented with a mass in the upper outer quadrant of the right breast measuring 25 x 15 x 7 cm. Mammography was performed and the mass was diagnosed as a liposarcoma. A wide excision was performed with a 2 cm margin of healthy tissue. The tumor was diagnosed histologically as a fibrous liposarcoma. The patient was discharged and her postoperative recovery was uneventful. We report a case of liposarcoma of the breast and discuss this rare malignant tumor together with the various diagnostic and therapeutic modalities used.     

Cryoloop vitrification of human day 3 cleavage-stage embryos: post-vitrification development, pregnancy outcomes and live births

Vitrification technology has shown great promise for cryopreservation of human embryos. The majority of this work has been with blastocyst-stage embryos. This report describes initial clinical results following vitrification of human embryos on day 3 of culture at the 6- to 8-cell stage. A total of 236 embryos were cryopreserved on cryoloops using a vitrification protocol. Warmed embryos were cultured until day 5 before transfer to the patient. The post-warming survival rate was 85%. The clinical pregnancy rate was 44% (34/77), and the implantation rate was 20% (40/201). In transfers where at least one warmed embryo reached the blastocyst stage by the day of transfer, the clinical pregnancy rate was 58% (28/48). The cryoloop was an excellent vessel for ultra-rapid cryopreservation of embryos. This study supports the effectiveness of a dimethylsulphoxide/ethylene glycol cryoprotectant combination for vitrification of human embryos at the 6- to 8-cell stage.     

Potential transition and post-transition metal sulfides as efficient electrodes for energy storage applications: review

Electrochemical energy storage has attracted much attention due to the common recognition of sustainable energy development. Transition metal sulfides and post-transition metal sulfides have been intensively been focused on due to their potential as electrode materials for energy storage applications in different types of capacitors such as supercapacitors and pseudocapacitors, which have high power density and long cycle life. Herein, the physicochemical properties of transition and post-transition metal sulfides, their typical synthesis, structural characterization, and electrochemical energy storage applications are reviewed. Various perspectives on the design and fabrication of transition and post-transition metal sulfides-based electrode materials having capacitive applications are discussed. This review further discusses various strategies to develop transition and/or post-transition metal sulfide heterostructured electrode-based self-powered photocapacitors with high energy storage efficiencies.

Electrochemical energy storage has attracted much attention due to the common recognition of sustainable energy development.     

An approach for evaluating the effects of dietary fiber polysaccharides on the human gut microbiome and plasma proteome

Increases in snack consumption associated with Westernized lifestyles provide an opportunity to introduce nutritious foods into poor diets. We describe two 10-wk-long open label, single group assignment human studies that measured the effects of two snack prototypes containing fiber preparations from two sustainable and scalable sources; the byproducts remaining after isolation of protein from the endosperm of peas and the vesicular pulp remaining after processing oranges for the manufacture of juices. The normal diets of study participants were supplemented with either a pea- or orange fiber-containing snack. We focused our analysis on quantifying the abundances of genes encoding carbohydrate-active enzymes (CAZymes) (glycoside hydrolases and polysaccharide lyases) in the fecal microbiome, mass spectrometric measurements of glycan structures (glycosidic linkages) in feces, plus aptamer-based assessment of levels of 1,300 plasma proteins reflecting a broad range of physiological functions. Computational methods for feature selection identified treatment-discriminatory changes in CAZyme genes that correlated with alterations in levels of fiber-associated glycosidic linkages; these changes in turn correlated with levels of plasma proteins representing diverse biological functions, including transforming growth factor type β/bone morphogenetic protein-mediated fibrosis, vascular endothelial growth factor-related angiogenesis, P38/MAPK-associated immune cell signaling, and obesity-associated hormonal regulators. The approach used represents a way to connect changes in consumer microbiomes produced by specific fiber types with host responses in the context of varying background diets.

Advances in our understanding of the role of the gut microbiome in regulating many aspects of human physiology hold the promise of evolving our view of human nutrition by establishing mechanistic connections between the foods we consume and how they affect health status. One manifestation of this effort is a series of studies, performed on well-phenotyped cohorts, that seek to relate features of gut microbial community composition (organisms, genes), dietary practices, and pre- and postprandial cardiometabolic responses to test meals (1–4). A key question raised by these initiatives relates to the nature of the “bioactive” components of foods. Specifically, what are the nutrients utilized by various gut community members or microbiome-encoded metabolic pathways? What products are produced by biotransformation of these nutrients? How are these products linked to specific host physiologic (or pathophysiologic) processes?Plant-derived dietary fibers represent a “poster child” for these efforts and illustrate the formidable challenges faced. The health benefits of dietary fibers are widely known, as is their inadequate representation in Western diets. However, natural fibers are structurally complex and highly diverse. They contain numerous, typically undefined polysaccharide structures and largely unspecified protein, lipid, and small molecule constituents. Their composition varies as a function of their origin (food staple and cultivar), the different methods employed to recover them from these sources, as well as the different techniques used to incorporate them into processed foods with acceptable organoleptic properties (5). Moreover, analyzing the host effects of metabolism of different fibers is confounded by the fact that there is substantial intra- and interpersonal variation in microbiome configuration (6, 7).Snacking is becoming an ever more dominant feature of daily life worldwide and thus provides an opportunity to introduce nutritious ingredients, such as fibers, into diets. However, obtaining structure-activity relationships for specific fiber types and their corresponding targets in the gut community is foundational for designing snack foods that evoke and/or reinforce microbiome responses that are beneficial to the host.Degradation of dietary polysaccharides is a function primarily performed by bacterial carbohydrate-active enzymes (CAZymes). The gut microbiome harbors tens of thousands of CAZyme genes belonging to at least 136 glycoside hydrolase (GH) and 29 polysaccharide lyase (PL) families [extrapolated and updated from El Kaoutari et al. (8)]. In contrast, the human genome only contains 98 GH and no PL genes (9), of which <20% contribute to the processing of dietary glycans.In the current study, we test the effects of dietary supplementation with two snack food prototypes, one containing pea fiber and the other orange fiber, in two pilot studies of overweight and obese individuals consuming their normal, unrestricted diets. Our strategy was to focus on fiber-associated changes in the abundances of microbial GH and PL genes to determine whether responses to the pea or orange fiber prototypes in the gut microbiome and host are decipherable against a background of varying dietary practices and starting microbiome configurations. Higher order singular value decomposition (10) was utilized as a feature selection tool to identify treatment-discriminating changes in GH and PL gene representation. Mass spectrometric assays of the levels of fecal glycan structures (glycosidic linkages) were subsequently performed and the results were correlated with changes in the abundances of treatment-discriminating GH and PL genes with known or predicted substrate specificities. Our analysis concluded by measuring changes in levels of 1,305 plasma proteins in each study participant as a function of fiber treatment and applying computational tools to identify links between these microbiome and plasma proteome changes in response to fiber consumption. Our results provide an approach, using pilot human studies, for selecting specific fiber preparations, plus informative microbiome and host biomarkers, that can be advanced to proof-of-concept clinical trials which assess their capacity for precise manipulation of microbiome and host features.