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Greater scientific understanding of cancer biology, the multistage process of carcinogenesis and tumour responses to conventional and targeted therapeutics have led to the development of combination therapies, for example, chemotherapy with immunotherapy, to achieve long-lasting efficacy and to target metastasis, which is currently the main cause of mortality in many types of cancer (Qin et al., 2020; Schirrmacher, 2019; Wu & Waxman, 2018; Yu et al., 2019). APPROACHES TO IMPROVE OUTCOMES OF EXISTING CANCER TREATMENTS The importance of precision medicine has been incorporated into developing cancer treatments as well as new strategies for decreasing the toxicity of chemotherapeutics and improving therapy outcomes. This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). Moreover, when applied in already developed cancers, nutritional interventions may stop or attenuate cancer progression by targeting cancer hallmarks, such as metastasis (Khadge et al., 2018; Sleeman, 2018). [Extracted from the article]

B Method/Summary of work b : We developed an NBA pipeline that (1) generates patient-specific disease networks by integrating and mapping multifaceted datasets (that include differentially expressed genes from patient's transcriptomic data, the deregulated transcription factors, disease-specific genes from GWAS studies and drug targets of interest) on to the large-scale protein-protein interaction network, (2) identifies key molecules and pathways in the patient-specific disease network and (3) scores each identified potential drug target based on the network connectivity score (that reflects signal propagation) and expression level. J Neurosci; 30: 573 - 582. https://doi.org/10.1523/JNEUROSCI.3295-09.2010 Oral Communications, Tuesday 7th September Oral Communications - Cardiovascular & Respiratory B OC001 b B The effects of allopurinol treatment in early period of monocrotaline-induced rat pulmonary hypertension model b Gokcen Telli SP 1 sp , Inci Kazkayasi SP 1 sp , E. Inci Ergonul SP 2 sp and Serdar Uma SP 1 sp SP 1 sp I Department of Pharmacology, Hacettepe University Faculty of Pharmacy; i SP 2 sp I Republic of Turkey Ministry of Health i B Introduction/Background & aims b : Along with the greater understanding of the pathogenesis of pulmonary hypertension (PH), one of the new treatment approaches is to evaluate the effectiveness of drugs used in diseases with pathologies similar to that of PH [1]. This study investigates the effect of this drug on cell death and proliferative signalling pathways in AML cells in vitro. [Extracted from the article]

Background and Purpose: 2‐Hydroxypropyl‐β‐cyclodextrin (HPCD) is an FDA approved vehicle for drug delivery and an efficient cholesterol‐lowering agent. HPCD was proposed to lower tissue cholesterol via multiple mechanisms including those mediated by oxysterols. CYP27A1 and CYP46A1 are the major oxysterol‐producing enzymes in the retina that convert cholesterol to 27‐ and 24‐hydroxycholesterol, respectively. We investigated whether HPCD treatments affected the retina of wild‐type and Cyp27a1−/−Cyp46a1−/− mice that do not produce the major retinal oxysterols. Experimental Approach HPCD administration was either by i.p., p.o. or s.c. Delivery to the retina was confirmed by angiography using the fluorescently labelled HPCD. Effects on the levels of retinal sterols, mRNA and proteins were evaluated by GC–MS, qRT‐PCR and label‐free approach, respectively. Key Results: In both wild‐type and Cyp27a1−/−Cyp46a1−/− mice, HPCD crossed the blood–retinal barrier when delivered i.p. and lowered the retinal cholesterol content when administered p.o. and s.c. In both genotypes, oral HPCD treatment affected the expression of cholesterol‐related genes as well as the proteins involved in endocytosis, lysosomal function and lipid homeostasis. Mechanistically, liver X receptors and the altered expression of Lipe (hormone‐sensitive lipase), Nceh1 (neutral cholesterol ester hydrolase 1) and NLTP (non‐specific lipid‐transfer protein) could mediate some of the HPCD effects. Conclusions and Implications: HPCD treatment altered retinal cholesterol homeostasis and is a potential therapeutic approach for the reduction of drusen and subretinal drusenoid deposits, cholesterol‐rich lesions and hallmarks of age‐related macular degeneration. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc [ABSTRACT FROM AUTHOR]

Background and Purpose: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear.Experimental Approach: We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted.Key Results: HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC.Conclusions and Implications: HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity. [ABSTRACT FROM AUTHOR]

Exosomes are a subset of extracellular vesicles essential for cell-cell communication in health and disease with the ability to transport nucleic acids, functional proteins and other metabolites. Their clinical use as diagnostic biomarkers and therapeutic carriers has become a major field of research over recent years, generating rapidly expanding scientific interest and financial investment. Their reduced immunogenicity compared to liposomes or viral vectors and their ability to cross major physiological barriers like the blood-brain barrier make them an appealing and innovative option as biomarkers and therapeutic agents. Here, we review the latest clinical developments of exosome biotechnology for diagnostic and therapeutic purposes, including the most recent COVID-19-related exosome-based clinical trials. We present current exosome engineering strategies for optimal clinical safety and efficacy, and assess the technology developed for good manufacturing practice compliant scaling up and storage approaches along with their limitations in pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Advances in the design of potential bone-selective drugs for the treatment of various bone-related diseases are creating exciting new directions for multiple unmet medical needs. For bone-related cancers, off-target/non-bone toxicities with current drugs represent a significant barrier to the quality of life of affected patients. For bone infections and osteomyelitis, bacterial biofilms on infected bones limit the efficacy of antibiotics because it is hard to access the bacteria with current approaches. Promising new experimental approaches to therapy, based on bone-targeting of drugs, have been used in animal models of these conditions and demonstrate improved efficacy and safety. The success of these drug-design strategies bodes well for the development of therapies with improved efficacy for the treatment of diseases affecting the skeleton. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc. [ABSTRACT FROM AUTHOR]