In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue

In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q][w]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (C = 0.11 μg/ml) was reached at 2 h (T) following oral administration of the compound at 10 mg/kg. The half-life was determined to be 2.6 h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20 mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 μg/ml and a correlation coefficient of r ≥ 0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases

Active immunisation of mice with GnRH lipopeptide vaccine candidates: importance of T helper or multi-dimer GnRH epitope

Active immunisation against gonadotropin releasing hormone (GnRH) is a potential alternative to surgical castration. This study focused on the development of a GnRH subunit lipopeptide vaccine. A library of vaccine candidates that contained one or more (up to eight) copies of monomeric or dimeric GnRH peptide antigen, an adjuvanting lipidic moiety based on lipoamino acids, and an additional T helper epitope, was synthesised by solid phase peptide synthesis. The candidates were evaluated in vivo in order to determine the minimal components of this vaccine necessary to induce a systemic immune response. BALB/c mice were immunised with GnRH lipopeptide conjugates, co-administered with or without Complete Freund's Adjuvant, followed by two additional immunisations. Significant GnRH-specific IgG titres were detected in sera obtained from mice immunised with four of the seven lipopeptides tested, with an increase in titres observed after successive immunisations. This study highlights the importance of for epitope optimisation and delivery system design when producing anti-hapten antibodies in vivo. The results of this study also contribute to the development of future clinical and veterinary immunocontraceptives

Developing an Integrated Crosscultural Approach to Teaching Persian Classical Music

Persian classical music is a complex expressive art form based on multi-sectional modal structures and melody-types, incorporating improvisation within a range of compositional genres. Historically, the music’s richly elaborated theory has been tacitly transmitted through the master-apprentice model where learning is based on imitation, memorisation and repetition of melodic forms within a model repertory known as radīf. Lack of agreement over theoretical principles and their codification has made Persian music challenging to learn, especially for those who are not immersed in the Iranian context. This study was inspired by a series of collaborative creative projects the researcher initiated with non-Iranian musicians after immigrating to Australia from Iran in 2009, in the context of which she was frequently asked to explain the workings of the Persian classical music system. Qualitative and autoethnographic in nature, its action-oriented research approach set out to devise, test and evaluate an efficient and effective cross-cultural means of transmitting the foundational tenets of Persian classical music to people living in time-challenged contexts outside Iran, one that did not compromise the music’s integrity. Musical content – theoretical concepts and repertoire – was organised and delivered in a series of workshops to two contrasting participant streams. Stream 1 involved non-Persian vocalists and instrumentalists who had attained at least a university undergraduate entry-level performance standard. It incorporated players of non-Persian instruments to expand the timbral palate. Stream 2 involved Persian non-musicians who were members of Sydney’s Iranian community and concentrated solely on voice. The workshop streams ran concurrently and for the most part independent of each other, although they converged for culminating performances. Adopting the role of teacher, the researcher developed and delivered the content in successive phases, each of which increased in the level of detail, difficulty and sophistication, and in the case of Stream 1, involved progressively fewer participants. Workshops and concerts were either video or audio recorded, and a two-way evaluation of the teaching and learning process was conducted. On the one hand, the research-teacher closely examined and reflected upon the instructional flow, identified key moments of pedagogical interaction with the participants, and then refined particular aspects for subsequent workshops in an attempt to increase the effectiveness and efficiency of the transmission process. On the other, participants in the project evaluated the teaching and learning process by way of brief surveys and semi-structured interviews, which data were coded and analysed in order to determine the extent to which the transmission process was effective, specifically with regard to striking an optimum balance of theoretical and practical knowledge and competence. One unanticipated outcome was the intercultural synergy that resulted from merging the two instructional streams in the rehearsals for the culminating concerts, and for the actual performances

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients’ survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis

Temporal evolution, most influential studies and sleeping beauties of the coronavirus literature

Following the outbreak of SARS-CoV-2 disease, within less than 8 months, the 50 years-old scholarly literature of coronaviruses grew to nearly three times larger than its size prior to 2020. Here, temporal evolution of the coronavirus literature over the last 30 years (N = 43,769) is analysed along with its subdomain of SARS-CoV-2 articles (N = 27,460) and the subdomain of reviews and meta-analytic studies (N = 1027). The analyses are conducted through the lenses of co-citation and bibliographic coupling of documents. (1) Of the N = 1204 review and meta-analytical articles of the coronavirus literature, nearly 88% have been published and indexed during the first 8 months of 2020, marking an unprecedented attention to reviews and meta-analyses in this domain, prompted by the SARS-CoV-2 pandemic. (2) The subset of 2020 SARS-CoV-2 articles is bibliographically distant from the rest of this literature published prior to 2020. Individual articles of the SARS-CoV-2 segment with a bridging role between the two bodies of articles (i.e., before and after 2020) are identifiable. (3) Furthermore, the degree of bibliographic coupling within the 2020 SARS-CoV-2 cluster is much poorer compared to the cluster of articles published prior to 2020. This could, in part, be explained by the higher diversity of topics that are studied in relation to SARS-CoV-2 compared to the literature of coronaviruses published prior to the SARS-CoV-2 disease. (4) The analyses on the subset of SARS-CoV-2 literature identified studies published prior to 2020 that have now proven highly instrumental in the development of various clusters of publications linked to SARS-CoV-2. In particular, the so-called “sleeping beauties” of the coronavirus literature with an awakening in 2020 were identified, i.e., previously published studies of this literature that had remained relatively unnoticed for several years but gained sudden traction in 2020 in the wake of the SARS-CoV-2 outbreak. This work documents the historical development of the literature on coronaviruses as an event-driven literature and as a domain that exhibited, arguably, the most exceptional case of publication burst in the history of science. It also demonstrates how scholarly efforts undertaken during peace time or prior to a disease outbreak could suddenly play a critical role in prevention and mitigation of health disasters caused by new diseases

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles

Lipid- and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain

Endomorphins are endogenous opioid peptides that cause potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, endomorphins are poorly suited to clinical applications because of low membrane permeability and a susceptibility to enzymatic degradation. Glycosylation and lipidation have proven to be two of the most robust approaches for the generation of new therapeutic endomorphin derivatives. Conjugation with lipoamino acids (LAA) confers an amphipathic character to the peptide, which improved interaction between the peptide and the lipid bilayer of the cell membranes, increasing permeability. Glycosylation can also improve peptide stability and blood brain barrier (BBB) transport. It is believed that an endocytotic mechanism (transcytosis) is responsible for the systemic delivery of water-soluble glycopeptides. This review discusses the application of glycosylation and lipidation strategies to improve the drug-like properties of endomorphins. Pharmacologically active endomorphin analogs with less adverse effects are also discussed