The viral approach to breast cancer immunotherapy

Despite years of intensive research, breast cancer remains the leading cause of death in women worldwide. New technologies including oncolytic virus therapies, virus, and phage display are among the most powerful and advanced methods that have emerged in recent years with potential applications in cancer prevention and treatment. Oncolytic virus therapy is an interesting strategy for cancer treatment. Presently, a number of viruses from different virus families are under laboratory and clinical investigation as oncolytic therapeutics. Oncolytic viruses (OVs) have been shown to be able to induce and initiate a systemic antitumor immune response. The possibility of application of a multimodal therapy using a combination of the OV therapy with immune checkpoint inhibitors and cancer antigen vaccination holds a great promise in the future of cancer immunotherapy. Display of immunologic peptides on bacterial viruses (bacteriophages) is also increasingly being considered as a new and strong cancer vaccine delivery strategy. In phage display immunotherapy, a peptide or protein antigen is presented by genetic fusions to the phage coat proteins, and the phage construct formulation acts as a protective or preventive vaccine against cancer. In our laboratory, we have recently tested a few peptides (E75, AE37, and GP2) derived from HER2/neu proto-oncogene as vaccine delivery modalities for the treatment of TUBO breast cancer xenograft tumors of BALB/c mice. Here, in this paper, we discuss the latest advancements in the applications of OVs and bacterial viruses display systems as new and advanced modalities in cancer immune therapeutics.     

Superior adaptation of aerobic rice under drought stress in Iran and validation test of linked SSR markers to major QTLs by MLM analysis across two years

Molecular Biology Reports - Drought is one of the biggest challenges for rice (Oryza sativa L.) production in rainfed areas. Developing “aerobic rice” cultivars could be a valuable...     

Comparative analysis of organophosphate degrading enzymes from diverse species

Different types of organophosphorous compounds constitute most potent pesticides. These chemicals attack the nervous system of living organisms causing death. Different organisms produce enzymes to degrade these chemicals. These enzymes are present in simple microorganisms from archaea, bacteria to complex eukaryotes like humans. A comparison of representative eight shortlisted enzymes involved in the degradation and inactivation of organophosphates from a wide range of organisms was performed to infer the basis of their common functionality. There is little sequence homology in these enzymes which results in divergent tertiary structures. The only feature that these enzymes seem to share is their amino acid composition. However, structural analysis has shown no significant similarities among this functionally similar group of organophosphate degrading enzymes.     

RelA1 gene control of Escherichia coli lipid structure and cell performance during glucose limited fed-batch conditions

At increasing glucose limitation, typical for fed-batch cultivation performance, cultivation of Escherichia coli (relA1) results in development of a lipid structure that radically differs from the wild type and is characterised by accumulation of neutral phospholipids and saturated fatty acids. The mutant can, furthermore, not change the level of cardiolipin, which is generally the hallmark of changes to severe glucose limitation. The result suggests an increased negative control in the mutant with respect to the flux to phosphatidyl glycerol and cardolipin as well as to unsaturated fatty acids. Opposite to the wild type, the cardiolipin-depleted membrane is more fragile with respect to sonication and osmotic chock, at severe limitation, and results in extensive foaming during the process. Protein leakage and cell lysis is, however, lower in the mutant most likely due to the increased amounts of saturated fatty acids, which might be a possible strategy to overcome the reduced amounts of membrane-strengthening cardiolipin. The membrane potential of the outer surface is negative, however less negative for the mutant. This was supported by aqueous two-phase extraction experiments which, furthermore indicated a difference in outer surface hydrofobicity. These findings suggest that the relA1 gene has a defined, but ppGpp-independent, role in cells with a slowly decreasing metabolism of glucose to control the membrane morphology.     

Design and synthesis of 1,3-diarylurea derivatives as selective cyclooxygenase (COX-2) inhibitors

A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC(50)=0.11 microM) with a high COX-2 selectivity index (SI=203.6) comparable to the reference drug celecoxib (COX-2 IC(50)=0.06 microM; COX-2 SI=405). The structure-activity data acquired indicate that the urea moiety constitutes a suitable scaffold to design new acyclic 1,3-diarylurea derivatives with selective COX-2 inhibitory activity.     

A role for Rac3 GTPase in the regulation of autophagy

The process of autophagy is situated at the intersection of multiple cell signaling pathways, including cell metabolism, growth, and death, and hence is subject to multiple forms of regulation. We previously reported that inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt), which catalyzes the final step in the post-translational prenylation of so-called CAAX proteins, results in the induction of autophagy which enhances cell death in some cancer cells. In this study, using siRNA-mediated knockdown of a group of small GTPases that are predicted Icmt substrates, we identify Rac3 GTPase as a negative regulator of the process of autophagy. Knockdown of Rac3, but not the closely related isoforms Rac1 and Rac2, results in induction of autophagy. Ectopic expression of Rac3, significantly rescues cells from autophagy and cell death induced by Icmt inhibition, strengthening the notion of an isoform-specific autophagy regulatory function of Rac3. This role of Rac3 was observed in multiple cell lines with varying Rac subtype expression profiles, suggesting its broad involvement in the process. The identification of this less-studied Rac member as a novel regulator provides new insight into autophagy and opens opportunities in identifying additional regulatory inputs of the process.     

LEI0258 Microsatellite Variability in Khorasan, Marandi, and Arian Chickens

Microsatellite LEI0258 is a genetic marker for chicken MHC haplotypes and can be used as an indicator of the influence of population genetics on immune responses. LEI0258 microsatellite variability in three Iranian indigenous chicken populations (Khorasan, Marandi, and Arian) was investigated. In total, 142 Khorasan, 42 Marandi, and 58 Arian chickens were examined. Collectively, 25 different alleles and 79 genotypes could be found. The observed levels of heterozygosity were 81% in Khorasan and Marandi and 34% in Arian chickens. Our results indicate that LEI0258 diversity in Marandi chickens is higher than in the other populations. Allelic diversity in Iranian chickens is relatively higher than in the local chicken breeds reported for Brazil and Vietnam.