Conventional DNA-Damaging Cancer Therapies and Emerging cGAS-STING Activation: A Review and Perspectives Regarding Immunotherapeutic Potential.

Many traditional cancer treatments such as radiation and chemotherapy are known to induce cellular DNA damage as part of their cytotoxic activity. The cGAS-STING signaling axis, a key member of the DNA damage response that acts as a sensor of foreign or aberrant cytosolic DNA, is helping to rationalize the DNA-damaging activity of these treatments and their emerging immunostimulatory capacity. Moreover, cGAS-STING, which is attracting considerable attention for its ability to promote antitumor immune responses, may fundamentally be able to address many of the barriers limiting the success of cancer immunotherapy strategies, including the immunosuppressive tumor microenvironment.

Novel human STING activation by hydrated-prenylated xanthones from Garcinia cowa.

Objectives: We investigate the anticancer activity and human stimulator of interferon genes pathway activation by a new hydrated-prenylated tetraoxygenated xanthone, garcicowanone I (1) and two known xanthones (2 and 3) that were isolated from the root bark of Garcinia cowa Roxb. ex Choisy.

Methods: The anticancer activity of each compound was evaluated by sulforhodamine B assay in immortalized cancer cell lines.

Exploiting the DNA Damaging Activity of Liposomal Low Dose Cytarabine for Cancer Immunotherapy.

Perhaps the greatest limitation for the continually advancing developments in cancer immunotherapy remains the immunosuppressive tumor microenvironment (TME). The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis is an emerging immunotherapy target, with the resulting type I interferons and transcription factors acting at several levels in both tumor and immune cells for the generation of adaptive T cell responses. The cGAS-STING axis activation by therapeutic agents that induce DNA damage, such as certain chemotherapies, continues to be reported, highlighting the importance of the interplay of this signaling pathway and the DNA damage response in cancer immunity/immunotherapy.

Synthesis & Evaluation of Novel Mannosylated Neoglycolipids for Liposomal Delivery System Applications.

Glycosylated NPs, including liposomes, are known to target various receptors involved in cellular carbohydrate transport, of which the mannoside binding receptors are attracting particular attention for their expression on various immune cells, cancers, and cells involved in maintaining central nervous system (CNS) integrity. As part of our interest in NP drug delivery, mannosylated glycoliposomal delivery systems formed from the self-assembly of amphiphilic neoglycolipids were developed, with a C-alkyl mannopyranoside (ML-C) being identified as a lead compoundcapable of entrapping, protecting, and improving the delivery of structurally diverse payloads. However, ML-C was not without limitations in both the synthesis of the glycolipids, and the physicochemical properties of the resulting glycoliposomes.

Iterated Local Search and Other Algorithms for Buffered Two-Machine Permutation Flow Shops with Constant Processing Times on One Machine.

The two-machine permutation flow shop scheduling problem with buffer is studied for the special case that all processing times on one of the two machines are equal to a constant c. This case is interesting because it occurs in various applications, for example, when one machine is a packing machine or when materials have to be transported. Different types of buffers and buffer usage are considered.

Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes.

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood-brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively.

Novel immunomodulatory properties of low dose cytarabine entrapped in a mannosylated cationic liposome.

Cancer treatment remains unsatisfactory with high rates of recurrence and metastasis. Immunomodulatory agents capable of promoting cellular antitumor immunity while inhibiting the local immunosuppressive tumor microenvironment could greatly improve cancer treatment. We have developed a multi-targeted mannosylated cationic liposome delivery system containing muramyl dipeptide (DS) and low doses of the chemotherapeutic agent cytarabine (Ara-C).

Assessing Neutralized Nicotine Distribution Using Mice Vaccinated with the Mucosal Conjugate Nicotine Vaccine.

Tobacco smoking continues to be a global epidemic and the leading preventable cause of cancer and cardiovascular disease. Nicotine vaccines have been investigated as an alternative to currently available smoking cessation strategies as a means to increase rates of success and long-term abstinence. Recently, we demonstrated that a mucosal nicotine vaccine was able to induce robust mucosal and systemic antibodies when delivered heterologously using intranasal and intramuscular routes.

Mannosylated glycoliposomes for the delivery of a peptide kappa opioid receptor antagonist to the brain.

Dynantin is a potent and selective synthetic polypeptide kappa opioid receptor antagonist which has potential antidepressant and anxiolytic-like therapeutic applications, however its clinical development has been hampered by plasma stability issues and poor penetration of the blood brain barrier. Targeted liposome delivery systems represent a promising and non-invasive approach to improving the delivery of therapeutic agents across the blood brain barrier. As part of our work focused on targeted drug delivery, we have developed a novel mannosylated liposome system.

Enhancing the Immune Response of a Nicotine Vaccine with Synthetic Small "Non-Natural" Peptides.

The addictive nature of nicotine is likely the most significant reason for the continued prevalence of tobacco smoking despite the widespread reports of its negative health effects. Nicotine vaccines are an alternative to the currently available smoking cessation treatments, which have limited efficacy. However, the nicotine hapten is non-immunogenic, and successful vaccine formulations to treat nicotine addiction require both effective adjuvants and delivery systems.

Repeat-Dose Toxicity Study Using the AFPL1-Conjugate Nicotine Vaccine in Male Sprague Dawley Rats.

Tobacco smoking is the cause of 20% of Canadian deaths per year. Nicotine vaccines present a promising alternative to traditional smoking cessation products, but to date, no vaccine has been able to move through all phases of clinical trials. We have previously demonstrated that the AFPL1-conjugate nicotine vaccine does not induce systemic or immunotoxicity in a mouse model and that a heterologous vaccination approach is more advantageous than the homologous routes to inducing mucosal and systemic anti-nicotine antibodies.

Case Reports of and Dextrocardia in Sprague Dawley Rats.

is a condition where there is a transposition of all internal organs from their normal anatomical location. This infrequent and rare congenital condition has been described in several species of mammals. Dextorcardia is a series of conditions associated with an abnormal congenital positioning of the heart, and is often associated with .

Assessing the immunogenicity and toxicity of the AFPL1-conjugate nicotine vaccine using heterologous and homologous vaccination routes.

Despite the increased risks of cancers and cardiovascular related diseases, tobacco smoking continues to be prevalent in the population due largely in part to the addictive nature of nicotine. Nicotine vaccines are an attractive alternative to the current smoking cessation options but have yet to be successful enough in clinical trials to reach the market due to a lack of neutralizing antibodies and inconsistent results. Using AFPL1 derived from the Cuban meningococcal vaccine as an adjuvant, we have previously published promising results with an intranasally administered nicotine vaccine.

Strengthening peptide-based drug activity with novel glyconanoparticle.

The therapeutic application of peptide-based drugs is significantly limited by the rapid proteolytic degradation that occurs when in blood. Encapsulation of these peptide structures within a delivery system, such as liposomes, can greatly improve both stability and target delivery. As part of our work focused on novel ambiphilic mannosylated neoglycolipids as targeted drug delivery systems, we have developed a C14-alkyl-mannopyranoside that forms self-assembled monodisperse liposomes.

Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity.

In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9-aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin-9-ylamino)propyl)-2-(thiophen-2-yl)-1,3-thiazinan-4-one (25; VR151) effectively killed many different cancer cell types, including eight breast cancer cell lines with different genetic background, two prostate cancer and two lung cancer cell lines. In contrast, compound 25 is less effective against non-cancer cells, suggesting it may be less toxic to humans.

Evaluating the immunogenicity of an intranasal vaccine against nicotine in mice using the Adjuvant Finlay Proteoliposome (AFPL1).

Tobacco smoking is recognized as a global pandemic resulting in 6 million deaths per year. Despite a variety of anti-smoking products available to aid with tobacco cessation, the majority of people who attempt to quit smoking relapse within 6 months due to the addictive nature of nicotine. An immunotherapy approach could offer a promising treatment option by inducing a potent selective antibody response against nicotine in order to block its distribution to the brain and its addictive effects in the central nervous system.

Cloning and enhancing production of a detergent- and organic-solvent-resistant nattokinase from Bacillus subtilis VTCC-DVN-12-01 by using an eight-protease-gene-deficient Bacillus subtilis WB800.

Background: Nattokinases/Subtilisins (EC 3.4.21.

Delivery of immunogens to mucosal immune system using an oral inactivated cholera vaccine: a new approach for development of oral vaccines.

Oral vaccines have several attractive features; however, due to several challenges, to date, only a limited number of oral vaccines are licensed. Over the past two decades, several oral vehicle delivery systems have been developed to address these challenges and deliver antigens to the target cells in the mucosal immune system. While the size of vehicle delivery systems, the quantity of components in the vehicle formulation, the dose of administration, and even the type of animals species, are important aspects in development of a suitable oral vaccine, our results showed that entrapment of inactivated Vibrio cholera, a component in the structure of Dukoral vaccine into oral vehicle delivery systems, is able to induce a more rigorous humoral immune response in the systemic compartment.

Antimicrobial effects of H4-(86-100), histogranin and related compounds--possible involvement of DNA gyrase.

Histone-derived antimicrobial peptides have been identified in various organisms from plants to humans. The rat histone H4 mRNA variants, H4-v.1 and rat histogranin (HNr) mRNAs, were recently reported to be involved in the synthesis of H4-(86-100) and its related peptide HNr, respectively.

Correlation between the expression of the histone H4 mRNA variant H4-v.1 and the levels of histone H4-(86-100) and H4-(89-102) (OGP) in various rat tissues and alveolar macrophages.

We studied the expression of the osteogenic and antinociceptive C-terminal histone H4-related peptide fragments, H4-(89-102) (OGP) and H4-(86-100), respectively, within various rat tissues and isolated alveolar macrophages (AM) by radioimmunoassay (RIA). OGP was located mainly within the bone marrow, spleen, thymus, and lungs whereas H4-(86-100) was more concentrated within the bone marrow, lymph nodes, spinal cord, pituitaries and thymus. The expression pattern of the two peptides showed similarities with the tissue expression pattern of the histone H4 mRNA variant H4-v.

Histogranin-like antinociceptive and anti-inflammatory derivatives of o-phenylenediamine and benzimidazole.

Histogranin (HN)-like nonpeptides were designed and synthesized using benzimidazole (compound 1) and o-phenylenediamine (compounds 2-7) as scaffolds for the attachment of phenolic hydroxyl and basic guanidino pharmacophoric elements present in HN. The benzimidazole derivative N-5-guanidinopentanamide-(2R)-yl-2-(p-hydroxybenzyl)-5-carboxybenzimidazole (1) and the o-phenylenediamine derivative N-5-guanidinopentanamide-(2S)-yl-2-N-(p-hydroxyphenylacetyl) phenylenediamine (2) were more potent analgesics than HN in both the mouse writhing (5.5 and 3.

Bioactive peptidic analogues and cyclostereoisomers of the minimal antinociceptive histogranin fragment-(7-10).

Novel analogues of the minimal antinociceptive histogranin (HN) fragment Gly(7)-Gln-Gly-Arg(10), in which amino acids in positions 8, 9, and 10 were replaced by lipophilic amino acids and corresponding d-amino acid residues in combination with N- to C-terminal cyclization, were synthesized and tested in various animal models of pain. All synthetic compounds were potent and efficacious analgesics in the mouse writhing test. Cyclic [-Gly-Ala-Tyr-d-Arg-] (9) and cyclic [-Gly p-Cl-Phe-Tyr-d-Arg-] (10) were the most potent analgesics, being 17 and 135 times as potent as HN, respectively (AD(50) of 1.