Risk groups defined by Recursive Partitioning Analysis of patients with colorectal adenocarcinoma treated with colorectal resection

<p>Abstract</p> <p>Background</p> <p>To define different prognostic groups of surgical colorectal adenocarcinoma patients derived from recursive partitioning analysis (RPA).</p> <p>Methods</p> <p>Ten thousand four hundred ninety four patients with colorectal adenocarcinoma underwent colorectal resection from Taiwan Cancer Database during 2003 to 2005 were included in this study. Exclusion criteria included those patients with stage IV disease or without number information of lymph nodes. For the definition of risk groups, the method of classification and regression tree was performed. Main primary outcome was 5-year cancer-specific survival.</p> <p>Results</p> <p>We identified six prognostic factors for cancer-specific survival, resulting in seven terminal nodes. Four risk groups were defined as following: Group 1 (mild risk, 1,698 patients), Group 2 (moderate risk, 3,129 patients), Group 3 (high risk, 4,605 patients) and Group 4 (very high risk, 1,062 patients). The 5-year cancer-specific survival for Group 1, 2, 3, and 4 was 86.6%, 62.7%, 55.9%, and 36.6%, respectively (p < 0.001). Hazard ratio of death was 2.13, 5.52 and 10.56 (95% confidence interval 1.74-2.60, 4.58-6.66 and 8.66-12.9, respectively) times for Group 2, 3, and 4 as compared to Group 1. The predictive capability of these grouping was also similar in terms of overall and progression-free survival.</p> <p>Conclusion</p> <p>The use of RPA offered an alternative grouping method that could predict the survival of patients who underwent surgery for colorectal adenocarcinoma.</p

Brn2 Is a Transcription Factor Regulating Keratinocyte Differentiation with a Possible Role in the Pathogenesis of Lichen Planus

Terminal differentiation of skin keratinocytes is a vertically directed multi-step process that is tightly controlled by the sequential expression of a variety of genes. In this study, we investigated the role of the POU domain-containing transcription factor Brn2 in keratinocyte differentiation. Immunohistochemical analysis showed that Brn2 is expressed primarily in the upper granular layer. Consistent with its epidermal localization, Brn2 expression was highly induced at 14 days after calcium treatment of cultured normal human epidermal keratinocytes. When Brn2 was overexpressed by adenoviral transduction, Brn2 led to increased expression of the differentiation-related genes involucrin, filaggrin, and loricrin in addition to inhibition of their proliferation. Chromatin immunoprecipitation demonstrated that Brn2 bound to the promoter regions of these differentiation-related genes. We injected the purified Brn2 adenovirus into rat skin, which led to a thickened epidermis with increased amounts of differentiation related markers. The histopathologic features of adenovirus-Brn2 injected skin tissues looked similar to the features of lichen planus, a human skin disease showing chronic inflammation and well-differentiated epidermal changes. Moreover, Brn2 is shown to be expressed in almost all cell nuclei of the thickened epidermis of lichen planus, and Brn2 also attracts T lymphocytes. Our results demonstrate that Brn2 is probably a transcriptional factor playing an important role in keratinocyte differentiation and probably also in the pathogenesis of lichen planus lesions

A Facile Strategy for In Situ Core-Template-Functionalizing Siliceous Hollow Nanospheres for Guest Species Entrapment

The shell wall-functionalized siliceous hollow nanospheres (SHNs) with functional molecules represent an important class of nanocarriers for a rich range of potential applications. Herein, a self-templated approach has been developed for the synthesis of in situ functionalized SHNs, in which the biocompatible long-chain polycarboxylates (i.e., polyacrylate, polyaspartate, gelatin) provide the framework for silica precursor deposition by simply controlling chain conformation with divalent metal ions (i.e., Ca2+, Sr2+), without the intervention of any external templates. Metal ions play crucial roles in the formation of organic vesicle templates by modulating the long chains of polymers and preventing them from separation by washing process. We also show that, by in situ functionalizing the shell wall of SHNs, it is capable of entrapping nearly an eightfold quantity of vitamin Bc in comparison to the bare bulk silica nanospheres. These results confirm the feasibility of guest species entrapment in the functionalized shell wall, and SHNs are effective carriers of guest (bio-)molecules potentially for a variety of biomedical applications. By rationally choosing the functional (self-templating) molecules, this concept may represent a general strategy for the production of functionalized silica hollow structures

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

Background: R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. Methodology/Principal Findings: We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPAR gamma and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. Conclusion: Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain

A Research Agenda for Helminth Diseases of Humans: Basic Research and Enabling Technologies to Support Control and Elimination of Helminthiases

Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host–parasite interactions and immunopathology; and 4) (invertebrate) host–parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases

Photoprotective Effect of a Polyopes affinis (Harvey) Kawaguchi and Wang (Halymeniaceae)-Derived Ethanol Extract on Human Keratinocytes

Purpose: To investigate the photoprotective effect of the ethanol extract of the red marine alga, Polyopes affinis (PAE) against ultraviolet B (UVB) radiation on cultured human keratinocytes.Methods: The 2',7'-dichlorodihydrofluorescein diacetate method was used to detect intracellular reactive oxygen species (ROS) generated by H2O2 treatment or UVB radiation. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT ) assay. Superoxide anion or hydroxyl radical was detected using an electron spin resonance spectrometer after reaction with the nitrone spin trap. Lipid peroxidation was assayed by determining the level of 8-isoprostane. Protein carbonyl formation was determined using a protein carbonyl ELISA kit. The degree of oxidative DNA damage was determined using an alkaline comet assay. Apoptosis was assessed by apoptotic bodies and DNA fragmentation.Results: PAE significantly scavenged the free radical 1,1-diphenyl-2-picrylhydrazyl, as well as hydrogen peroxide- and UVB-induced intracellular ROS. Furthermore, PAE showed 23 % scavenging effect of the superoxide anion and 33 % of the hydroxyl radical. PAE also absorbed UVB rays in the 280 – 320 nm range. PAE significantly decreased cellular damage resulting from UVB-induced oxidative stress to lipids, proteins, and DNA. Furthermore, PAE-treated keratinocytes showed significant reduction in UVB-induced apoptosis, as exemplified by fewer apoptotic bodies and reduced DNA fragmentation.Conclusion: These results suggest that PAE protects keratinocytes against UVB-induced oxidative stress by absorbing UVB rays and scavenging ROS, thereby reducing injury to cellular constituents.Keywords: Human keratinocytes, Polyopes affinis, Reactive oxygen species, Red algae, Ultraviolet B, Apoptosis, DNA fragmentatio