• 

  Investigating the expression and function of aldehyde dehydrogenases in prostate cancer. Probing the expression and function of ALDHs using chemical probes, drugs and siRNA

  Pors, Klaus; Maitland, N.J.; Phillips, Roger M.; Sadiq, Maria (University of BradfordFaculty of Life Sciences, 2017)

  Castration-resistant prostate cancer (CRPC) remains an aggressive incurable disease in men mainly due to treatment resistance. Current treatments do not effectively eradicate cancer stem cells (CSCs), which play a pivotal role in tumour maintenance, progression and drug resistance. Aldehyde dehydrogenases (ALDHs) have been used in some tumour types as CSC markers. Their high expression and high functional activity found in CSCs is also associated with drug resistance. Emerging evidence suggests deregulation of certain ALDH isoforms have implications in cancer. The role of ALDHs in prostate cancer as potential biomarkers and therapeutic targets has not been fully explored yet. Accordingly, this study investigated the expression, regulation and function of selected ALDH isoforms in prostate cancer. This study showed that ALDH1A3, ALDH1B1, ALDH2 and ALDH7A1 are highly expressed in primary prostate cancer cells (n=9) compared to benign (n=9) prostate cells. The expression of ALDH1A3 was high in the stem cells (SCs) (n=3) as well as the more differentiated counterparts (n=16). Treatment of both benign and malignant primary prostate cancer cells with all-trans retinoic acid (atRA) also resulted in increased expression of ALDH1A3 and ALDH3A1, supporting a feedback loop between atRA and ALDHs. Furthermore, SerBob, Bob and LNCaP cells were sensitive to treatment with epigenetic drugs and led to significantly higher expression of ALDH1A2, ALDH3A1 and ALDH7A1 respectively. Importantly, siRNA suppression of ALDH1A3 and ALDH7A1 led to reduced SC properties of primary prostate cultures including reduced cell viability, migration and colony formation, and increased differentiation of transit amplifying (TA) cells to committed basal (CB) cells. Novel ALDH-affinic probes showed reduced cell viability of primary prostate epithelial cultures as a single agent and also when used in combination with docetaxel. The results indicate the potential of using ALDH-affinic compounds as single agents for therapeutic intervention or in combination with docetaxel to sensitise resistant cells to this anticancer drug. The data in this thesis provides novel findings, which supports ALDH1A2, -1A3 and -7A1 as potential biomarkers and/or therapeutic targets for drug intervention. Although, a study analysing a larger number of samples is necessary to fully understand ALDH isoform expression in CSC, TA and CB cells it is envisaged that an ALDH-targeted therapy have potential in future treatment strategies for prostate cancer.
• 

  Engineering of Amorphous Active Pharmaceutical Ingredients by Sonoprecipitation and Spray Drying Pre-and Post-Processing Pharmaceutical Characterisation. Pre- and Post-Processing Physicochemical and Micromeritic Characterisation of Active Pharmaceutical Ingredients

  Paluch, Krzysztof J.; Paradkar, Anant R.; Abdalmaula, Hanan A.S. (University of BradfordSchool of Pharmacy and Medical Sciences. Faculty of Life Sciences, 2019)

  Amorphous active pharmaceutical ingredients remain in the research focus as an avenue to achieve a better solubility of drugs. Several processing techniques are applied to produce amorphous materials. Main two approaches applied to production of amorphous phases are comminution of crystalline materials in order to break down molecular long-range order of their crystal lattices and amorphous phase precipitation from solutions. This thesis is focused on processing challenges in preparation of amorphous API phases from solutions by spray drying and evaporative antisolvent sonoprecipitation. Budesonide (BUD) and simvastatin (SMV) were used as model poorly soluble APIs. Amorphous phases of relatively low-glass transition (Tg) APIs are physically unstable and crystallise upon storage and/or processing conditions. To tackle this issue, for the first time in this work a selection of polyvinylpyrrolidone vinyl acetate (PVP-VA) co-polymers has been applied to investigate impact of sonoprecipitation processing parameters and a composition of PVP-VA on physicochemical and micromeritic properties of BUD/PVP-VA nanoparticulate composites. Studies confirmed that in solid-state BUD is miscible with PVP-VA polymers. Application of factorial design revealed that processing parameters: polymer type, surfactant concentrations, time and amplitude of sonication impact the entrapment efficiency, drug loading, polydispersity and particle size properties of produced nanoparticles. The largest fraction of polymer to drug in produced nanoparticles has been achieved with PVP VA E-535. As it is known that polymer content in formulation of APIs may slow down its dissolution, novel approach to processing and dissolution enhancement of amorphous composites of SMV produced by spray drying has been applied. Introduction of easily crystallising inorganic salt- sodium chloride into spray drying feed rendered SMV-polyvinyl pyrrolidone (PVP) amorphous microparticles loaded with nanocrystalline NaCl. Addition of NaCl successfully facilitated generation of discrete microparticles post spray drying with low-Tg polymers, which otherwise were not processable as binary mixtures. In addition, NaCl content aided tabletability and dissolution of amorphous API composites with more viscous and high-Tg PVP polymers. Studies confirmed that application of factorial design facilitates robust design of production process of amorphous nanocomposites by sonoprecipitation as well as that introduction of soluble nanocrystalline phase into amorphous binary solid dispersion by spray drying aids its processing and dissolution.
• Development of Concrete Mixtures Based Entirely on Construction and Demolition Waste and Assessment of Parameters Influencing the Compressive Strength

  Yildirim, G.; Ozcelikci, E.; Alhawat, Musab M.; Ashour, Ashraf F. (2023-06)

  Demolition and reconstruction of degrading structures alongside with the repetitive repair, maintenance, and renovation applications create significant amounts of construction and demolition waste (CDW), which needs proper tackling. The main emphasis of this study has therefore been placed on the development of concrete mixtures with components (i.e., aggregates and binder) coming entirely from CDW. As the binding phase, powdered CDW-based masonry units, concrete and glass were used collectively as precursors to obtain geopolymer binders, which were then incorporated with CDW-based fine and coarse concrete aggregates. Together with the entirely CDW-based concretes, designs were also proposed for companion mixtures with mainstream precursors (e.g., fly ash and slag) occupying some part of the CDW-based precursor combination. Sodium hydroxide (NaOH), sodium silicate (Na2SiO3) and calcium hydroxide (Ca[OH]2) were used at various concentrations and combinations as the alkaline activators. Several factors that have impact on the compressive strength results of concrete mixtures, such as mainstream precursor replacement rate, al-kaline molar concentrations, aggregate-to-binder ratios and curing conditions, were considered and these were also backed by the micro-structural analyses. Our results showed that through proper optimiza-tion of the design factors, it is possible to manufacture concrete mix-tures entirely out of CDW with compressive strength results able to reach up to 40 MPa under ambient curing. Current research is believed to be very likely to promote more innovative and up-to-date techniques to upcycle CDW, which are mostly downcycled through basic practices of road base/sub-base filling, encouraging further research and increas-ing the awareness in CDW issue.
• 

  Examining the Relationship Between Blockchain Capabilities and Organizational Performance in the Indian Banking Sector

  Garg, P.; Gupta, B.; Kapil, K.N.; Sivarajah, Uthayasankar; Gupta, S. (2023-03-20)

  Blockchain has enormous capabilities to transform traditional business models in countless ways. Banks in India are building collaborative blockchain ecosystems to create an innovative business model and disrupt the traditional one to create more competitive advantage. This study’s purpose was to examine the relationship between blockchain capabilities (BCC), competitive advantage (CA), and organizational performance (OP), as well as evaluate CA’s mediating role in the relationship between BCC and OP. In this context, a scientific research model, including a hypothesis, has been developed from extant literature. The proposed model was tested using statistical data collected from blockchain specialists, blockchain product marketing managers, experts in future and emergent technology, and banking, finance, and tech managers or executives who are involved in planning and deploying practical blockchain in the financial sector. Data were analyzed and tested using AMOS 22.0 and a process macro using a sample comprising 289 responses. Our empirical results indicated a significant positive relationship between BCC, CA, and OP, as well as a relationship between BCC and OP, partially mediated by CA. This paper took an original approach and contributes to the literature on this subject to understand CA’s mediating role in the relationship between BCC and OP in the Indian banking sector.
• 

  Chain-Extendable Crosslinked Hydrogels Using Branching RAFT Modification

  Rimmer, Stephen; Spencer, P.; Nocita, D.; Sweeney, John; Harrison, M.; Swift, Thomas (2023-03-17)

  Functional crosslinked hydrogels were prepared from 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AA). The acid monomer was incorporated both via copolymerization and chain extension of a branching, reversible addition–fragmentation chain-transfer agent incorporated into the crosslinked polymer gel. The hydrogels were intolerant to high levels of acidic copolymerization as the acrylic acid weakened the ethylene glycol dimethacrylate (EGDMA) crosslinked network. Hydrogels made from HEMA, EGDMA and a branching RAFT agent provide the network with loose-chain end functionality that can be retained for subsequent chain extension. Traditional methods of surface functionalization have the downside of potentially creating a high volume of homopolymerization in the solution. Branching RAFT comonomers act as versatile anchor sites by which additional polymerization chain extension reactions can be carried out. Acrylic acid grafted onto HEMA–EGDMA hydrogels showed higher mechanical strength than the equivalent statistical copolymer networks and was shown to have functionality as an electrostatic binder of cationic flocculants.

View more