Immunostimulatory CpG oligonucleotides enhance the immune response of anti-idiotype vaccine that mimics carcinoembryonic antigen

We have developed and characterized a monoclonal anti-idiotype (Id) antibody, designated 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate for CEA. Anti-Id 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colorectal cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Immunostimulatory oliogonucleotides containing the unmethylated CpG motif (CpG ODN) are potent inducers of both innate and adaptive immunity and can serve as suitable vaccine adjuvants. In this study, using the CEA-transduced MC-38 murine colon carcinoma model in syngeneic C57BL/6 mice, we assessed whether a select CpG ODN (1826) can function as immune adjuvant in immunization of mice with anti-Id 3H1. Complete Freund's adjuvant (FA) was used as a gold standard in this system. A single immunization of 3H1 mixed with CpG ODN 1826 was sufficient to induce measurable anti-CEA immunity in na?ve mice. However, 3 immunizations every other week were necessary to obtain and sustain peak immune reactivity over a long period of time. With FA and 3H1, single immunization was ineffective and multiple immunizations (5 to 6) were needed to achieve and sustain peak immunity. Anti-CEA antibody reactivity was comparable in both groups, but cellular immune reactivity as measured by immune splenic lymphocyte T cell proliferation and cytoxicity assay was slightly higher in the CpG ODN group. Mice immunized with 3H1 and either CpG ODN or FA were protected from challenge by lethal doses of MC-38-CEA cells. However, the degree of protection was slightly higher and the duration of survival was somewhat longer in the group of mice treated with 3H1 plus CpG ODN. Thus, CpG ODN 1826 was faster than FA in increasing anti-tumor immunity induced by anti-Id 3H1 immunization in this prophylactic model.     

Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4

Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.     

New species and records of orbiliaceous fungi from Georgia,USA

Orbilia georgiana and O. renispora are described as new species to science, in addition, O. eucalypti, O. occulta, and O. xanthoguttulata are reported based on collections taken from the state of Georgia, USA. Orbilia xanthoguttulata is a new record for North America. The morphology of all species is described based on both sexual and asexual morphs. Asexual morphs were obtained from ascospore isolates, from which also DNA was extracted and used to amplify rDNA genes (ITS and LSU) for phylogenetic comparison.     

Orbilia tianmushanensis sp. nov., a new member of the O. luteorubella group with an unusual asexual morph

A new species of Orbilia related to O. luteorubella is described mainly based on morphological characters of its asexual morph and molecular data. The sexual morph does not significantly differ from O. luteorubella, whereas the asexual morph obtained from its ascospore isolate resembles members of the non-predacious genus Dactylella, because it has fusiform phragmoconidia borne singly at the apex of conidiophores. Phylogenetic analysis showed that this strain clustered with a clade that included available strains of the O. luteorubella aggregate and was distant from all analysed Dactylella species. Within this clade, the new strain fell between species with filiform conidia and those of a Pseudotripoconidium anamorph. By combining morphological and phylogenetic analyses, we conclude that our isolate belongs to a new taxon. Pleomorphism of the new taxon is described and discussed.     

A comparative study of two community-based conservation models in Nepal

Conservation areas (CAs) and community forests (CFs) are generally considered to be two successful community-based conservation (CBC) models in Nepal. Nepal’s two CAs are administered by a nongovernmental organization (NGO), and all of its CFs are administered by a government agency (GA). The goal of this research is to compare and contrast these two models using quantitative and qualitative data collected through field research in the Annapurna Conservation Area in the summer of 2007 and adjacent CFs in the fall of 2008. The Conservation Area Management Committee (CAMC) and the Community Forest User Committee (CFUC) are the functional decision-making entities at the local level in CAs and CFs, respectively. We conducted one-on-one semi-structured interviews with 66 executive members of 10 CAMCs and 67 members of 9 CFUCs. While both models appear to have performed well overall, the CA under the direction of the NGO appears to have fared better with regard to (i) developing trust of local constituencies, (ii) garnering favorable attitudes among villagers, (iii) building capacity of executive members, and (iv) improving standards of living. We suggest that the particular accountabilities associated with NGOs may situate them in a better position to cultivate local governance than state entities on their own.     

Xerombrophila crystallifera, a new genus and species in the Helotiales

Xerombrophila, a new member of the Helotiales, is erected for a previously undescribed species that macroscopically resembles genera such as Phaeohelotium or Pezicula. The new species, for which we propose the name X. crystallifera, is characterized by a strong gelatinization of the medullary excipulum as well as the covering layer of the ectal excipulum, by the presence of abundant octahedral crystals, asci with an euamyloid apical ring that resembles the Calycina-type, and paraphyses containing refractive vacuoles. It can also be distinguished from members of both Ombrophila and Phaeohelotium in that it is desiccation-tolerant by surviving several weeks in the dry state. The species appears to be confined to xeric bark of Salix and was exclusively found over waterlogged soil, irrespective of being acidic or calcareous. It is known from various planar and colline areas of temperate Europe, and can be found throughout the year. Phylogenetic analysis of partial LSU sequences positions X. crystallifera as a sister taxon of a clade within the Helotiaceae s.l. that includes Ascocoryne, Chloroscypha, Gelatinodiscus, Neobulgaria and "Sarcoleotia" turficola.     

Identifying Novel Drug Indications through Automated Reasoning

Background

With the large amount of pharmacological and biological knowledge available in literature, finding novel drug indications for existing drugs using in silico approaches has become increasingly feasible. Typical literature-based approaches generate new hypotheses in the form of protein-protein interactions networks by means of linking concepts based on their cooccurrences within abstracts. However, this kind of approaches tends to generate too many hypotheses, and identifying new drug indications from large networks can be a time-consuming process.

Methodology

In this work, we developed a method that acquires the necessary facts from literature and knowledge bases, and identifies new drug indications through automated reasoning. This is achieved by encoding the molecular effects caused by drug-target interactions and links to various diseases and drug mechanism as domain knowledge in AnsProlog, a declarative language that is useful for automated reasoning, including reasoning with incomplete information. Unlike other literature-based approaches, our approach is more fine-grained, especially in identifying indirect relationships for drug indications.

Conclusion/Significance

To evaluate the capability of our approach in inferring novel drug indications, we applied our method to 943 drugs from DrugBank and asked if any of these drugs have potential anti-cancer activities based on information on their targets and molecular interaction types alone. A total of 507 drugs were found to have the potential to be used for cancer treatments. Among the potential anti-cancer drugs, 67 out of 81 drugs (a recall of 82.7%) are indeed known cancer drugs. In addition, 144 out of 289 drugs (a recall of 49.8%) are non-cancer drugs that are currently tested in clinical trials for cancer treatments. These results suggest that our method is able to infer drug indications (original or alternative) based on their molecular targets and interactions alone and has the potential to discover novel drug indications for existing drugs.