DORA
DORA (De Montfort Open Research Archive) is De Montfort University's research repository. It forms the primary public and institutional record of DMU research outputs. The breadth of research at DMU means that these outputs include articles, conference papers, books, book chapters, and other material available in a digital form. The record for each item contains descriptive information as well as, where possible, a version of the final research output. DORA also provides access to DMU PhD theses. This includes most PhD produced from 2009 onwards.
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Recent Submissions
Operation Enigma: A novel case study investigation
(2025-05-12) Able, Joel; Russell, Alexandra; Donovan, Gemma; Nichols-Drew, Leisa
De Montfort University is the only UK university to be a United Nations Academic Impact SDG (Sustainable Development Development) Chair Hub for SDG11: Sustainable Cities and Communities. We embrace the SDG16 ethos within the Chartered Society of Forensic Sciences accredited BSc Forensic Science undergraduate degree. Experiential/Participatory learning is integral to our curriculum, aligned to the Criminal Justice System: Crime Scene, Forensic Laboratory, and Court. We implement a Tri-modal approach for student active learning experiences: physical (utilising on campus facilities such as the crime scene house and non-residential space, industry specification laboratory facilities, vehicle and the former Leicester Crown and Magistrate courtrooms), integrating contextual information (provided by academic colleagues from our practitioner casework experience and research informed teaching portfolios), with the virtual world (embracing innovative and immersive technologies; asynchronously within our VLE, and synchronously; in timetabled sessions). Here, we showcase Operation Enigma – a unique organised crime group case study created in a cross-Faculty and interdisciplinary partnership, involving a County Lines criminal investigation, incorporating crime scenes, seminars, and practical laboratory classes. Linking the entirety of Operation Enigma is digital technology (mobile phone, CCTV, social media, and background intelligence). This is a transformative heutagogy, integrating professional expectations, via co-creation, peer feedback, reflection, and problem-based learning to enhance students’ Graduate Attributes, with development of 21 century employability skills (collaboration, critical analysis, communication, creative thinking). Operation Enigma demonstrates the paramount importance of authentic real-world learning. Ultimately, this will interest global Criminal Justice educators (academics, practitioners, trainers) as to innovative and immersive learning opportunities.
THE DESIGN OF A NOVEL ANTI-TUMOUR DRUG DELIVERY SYSTEM USING IMMUNE-DERIVED CELLS.
(De Montfort University, 1992-05) LILLEY, JACQUELINE CAROL
Exploitation of the natural ability of some immune-derived cells to target and kill tumour cells has been approached by use of the cells in conjunction with liposomes which have been used to carry a wide variety of therapeutic agents. The proposed delivery device combines the two approaches of targeting liposomes specifically to tumours and metastases and the adoptive immunotherapy of monocytes and/or macrophages. It involves encapsulation of chemotherapeutic drug within a liposomal matrix which affords protection from the host-immune response by uptake of the drug-liposome, combination into macrophages. Liposomes were prepared containing either the fluorescent probe carboxyfluorescein located in the liposomal aqueous phase, or the anticancer drugs doxorubicin or mitoxantrone which located in the lipid bilayer. Unelicited murine peritoneal macrophages were chosen as the mcrophage model for the present study and attempts were made to isolate them from murine peritoneal exudate. The isolation of monocytes from human whole blood was also conducted since it would be necessary to carry out further studies in a human model. The number of unelicited murine peritoneal macrophages available for injection was maximised by culture of the macrophages in polyallomer centrifuge tubes- a substratum to which minimum adherence and a similar level of phagocytosis occurred compared to plastic or Teflon film. The effect of lipid type, charge, pre-incubation of liposomes in serum and liposomal concentration upon uptake of carboxyfluorescein liposomes by murine peritoneal macrophages in vitro was found to be negligible with respect to the concentration of carboxyfluorescein ingested. However, uptake in vivo of i.p. injected mitoxantrone and doxorubicin liposomes was considerably higher than that observed in vitro and the many liposomes ingested occupied a large volume of intracellular space within the macrophages. Furthermore, the macrophages were observed to retain their viability after liposome internalisation. Observation of cells using a laser light confocal microscope revealed that mitoxantrone was retained in the internalised liposomes compared to the doxorubicin of which much was released and collected at the nuclear membrane as was also observed with the free doxorubicin. The mitoxantrone liposomes were considerably less toxic to a human breast cancer cell line (MCF-7) in vitro than free mitoxantrone but more toxic than the drugfree liposomes which had a negligible cytotoxic effect. The murine peritoneal macrophages (MPM) containing mitoxantrone liposomes were more toxic in a 10:1 than a 1:1 MPM:MCF-7 ratio. This suggested that the toxicity was dependent upon the concentration of available free mitoxantrone which is consistent with observations by others for the intact release of doxorubicin from macrophages. Liposomes were labelled with [3H]-mitoxantrone and their distribution was observed in mice alone and within murine peritoneal macrophages loaded in vivo. The label was located predominantly in the liver, spleen, gut and carcass one hour after i.v. injection into a litter mate which revealed that the macrophages containing the liposomes were not trapped in the lungs and were therefore capable of reaching a tumour target.
Self-learning brainstorm optimization for synchronization of operations and maintenance toward dual resource-constrained flexible job shops
(Elsevier, 2025-05-10) Yan, Qi; Wang, Hongfeng; Yang, Shengxiang; Fu, Yaping
In semi-automated flexible job shop manufacturing scenarios such as furniture customization and circuit board assembly, machine and worker resources need to be flexibly assigned to the processing of each operation, to improve the efficiency of human-machine collaboration and reduce the makespan. Driven by the practical need, the dual resource-constrained flexible job shop scheduling problem (DRCFJSP) has gradually attracted attention from the academic community. However, preventive maintenance (PM) of machines as a key constraint tends to be overlooked in previous research. In this study, a synchronization optimization of the DRCFJSP and PM scheduling is proposed and a joint decision-making model is established, to strike a balance between flexible job shop operations and maintenance. A self-learning brainstorm optimization algorithm (SLBOA) is developed to solve the model. In the SLBOA, an adaptive K-means algorithm based on the silhouette method is employed for flexible clustering, and four global update strategies are adaptively selected using the Q-learning algorithm to facilitate an effective interaction of individuals between different clusters. Furthermore, two knowledge-based local search methods are used to enhance the exploration of elite solutions within the necessary neighborhood structure. Experimental results show that the SLBOA outperforms four state-of-the-art algorithms in solving the proposed DRCFJSP with PM.
Development of less toxic analogues of fascaplysin as novel therapeutic agents for the treatment of cancer
(De Montfort University, 2007-03) Mahale, Sachin Govindrao
Cyclin-dependent kinase 4 (Cdk4) represents a crucially important target for the treatment of cancer because most human cancers are characterised by over-expression of its activating partner cyclin Dl (product of an oncogene), loss of the natural Cdk4 specific inhibitor p 16 INK4A or mutation in Cdk4' s catalytic subunit. Even the target of Cdk4, pRb, is found to be functionally inactive in many human tumours. All of these aberrations can cause deregulated cell growth, resulting in tumour formation. Therefore, a small synthetic molecule or a natural product that specifically and potently inhibits the kinase activity of Cdk4 in vitro and prevents cell growth and tumour volume in vivo could be of immense therapeutic value for the treatment of cancer.
Fascaplysin is a marine natural product which is a potent Cdk4-specific inhibitor. However, fascaplysin also intercalates DNA resulting in S phase block in the cell division cycle and unusual toxicity at the cellular level. The purpose of these studies was to develop a less toxic analogue of fascaplysin that abolishes fascaplysin's DNA binding capacity but maintains its potency to inhibit Cdk4 so as to obtain a novel therapeutic agent for the treatment of cancer.
The newly synthesized compounds (based on the structure of fascaplysin) were screened in five different Cdk enzyme assays: Cdk4-cyclin Dl, Cdk2-cyclin A, Cdk2-cyclin E, Cdkl-cyclin B1 and Cdk9-cyclin Tl. The results from these assays led to the identification of compounds that specifically inhibit Cdk4 enzyme activity in vitro (i.e. compounds that are, at least, 10-fold more potent in inhibiting Cdk4 than Cdk2, Cdkl or Cdk9). Interestingly, none of fascaplysin's analogues showed any interaction or intercalation with double-stranded DNA, proving that fascaplysin's ability to inhibit Cdk4 specifically can be separated from its deleterious DNA intercalating characteristic.
These structural analogues of fascaplysin were tested for their ability to inhibit cancer cell growth in vitro. We have succeeded in identifying novel molecules (from the screening of four different series of compounds) which inhibit the growth of cancer cells in vitro at low micro-molar concentrations. The most active compounds CAI 99, CA224, AJW089 and DE002 inhibited growth of cancer cells at an average IC50 concentration of 7, 4.2, 2 and 0.74 µM respectively. The effects on the long term survival (colony forming ability) of cancer cells in vitro followed by the treatment with the compounds were also evaluated. Colony forming ability usually reflects an anticancer compound's efficacy in viva. It was found that these compounds significantly reduce the colony forming ability of cancer cells in vitro.
Compounds showing potent anti-proliferative effects were studied further for their effects on the cell division cycle. To our surprise, some of the analogues manifested not only the expected Cdk4-specific inhibition by blocking at the G0/G1 phase of the cell cycle but also exhibited a G2/M phase block in a Cdk-independent manner. The unexpected G2/M block posed many questions regarding the possible dual mechanism of action of these compounds. Interestingly, we found that the fascaplysin analogues that show profound block at G2/M phase also inhibit tubulin polymerization both in an in vitro cell-free assay as well as in a cell-based assay. Further experiments were performed to evaluate the effect of these compounds on the expression levels of the tumour suppressor proteins pRb and p53 by Western blotting. It was found that CA199 and CA224 enhanced the expression levels of p53 but did not alter the expression levels of the pRb protein. CA 199 and CA224 were also found to induce the levels of cell cycle inhibitory proteins p27KJPJ and p21CIPJ/WAFJ _ Western analyses to check the phosphorylation status ofpRb protein at Cdk4 specific sites (Ser780, Ser795 and Ser8071811) indicated that the block of cancer cell growth at G0/G1 was mediated by Cdk4.
Although most of the synthesised molecules are Cdk4-specific, yet they do not manifest their cellular activities only via Cdk4. Intriguingly, we confirm that some selected compounds manifest their cellular action by targeting multiple sites in the cancer cell division cycle. We also show that two of these selected compounds are highly efficacious in inhibiting tumour growth in human xenograft-SCID mice models. In animal studies, CA224 and DE002 significantly inhibited the in viva tumour growth ofHCTl 16 (human colon cancer) and NCI-H460 (human lung cancer).
Walsall Strategy for Tackling Hate: Building Resilient Communities 2025-2029
(2025-05-07) Sadique, Kim