Oncolytic vaccinia virus for the treatment of liver cancer

Aims: Current treatment of colorectal cancer (CRC) liver metastases has a success rate of 50% 5-year survival, and recurrence rates of 50%. There is therefore still a need for a novel treatment modality. We aimed to examine the ability of JX-594 to preferentially replicate in and kill CRLM in vitro and ex vivo, and induce immunemediated tumour cytotoxicity by activation of natural killer (NK) cells. Methods: The Wyeth strain of vaccinia virus has been genetically manipulated to encode for granulocyte macrophage colony stimulating factor (JX-594-GM-CSFfLuc) and green fluorescent protein (JX-594-GM-CSF-GFP) in the disrupted thymidine kinase locus. Viability assays and Enzyme Linked Immunoabsorbent Assay (ELISA) was used to confirm tumour cell killing and production of inflammatory cytokines when CRC cell lines were infected with JX-594. Viral replication in vitro was investigated by plaque assay and using an ex vivo ‘tissue core’ method. Induction of the innate immune response was measured by upregulation of activatory markers on virus-treated-NK cells and monocytes by flow cytometry and anti-tumour cytotoxicity by chromium release. Results: JX-594 can directly lyse CRC cell lines, with greater lysis and replication (up to 250-fold) in cells with upregulated surface EGFR. JX-594 treatment resulted in substantial expression of GM-CSF and induction of inflammatory cytokines within the tumour microenvironment, and inhibition of anti-inflammatory and proangiogenic cytokines. Ex vivo infection of CRLM with JX-594-GFP-GM-CSF resulted in tumour-specific GFP and GM-CSF expression. Treatment of NK cells with JX-594-GM-CSF led to activation, degranulation and increased cytotoxicity against CRC cell targets. This was dependent on the presence of CD14+ve monocytes, which acquired an antigen-presenting phenotype (CD86+veCD11c+veClassIIDR+ve). Conclusions: JX-594 holds promise as a novel treatment modality for disseminated CRC. Direct tumour-specific lysis and transgene expression and the induction of tumour-specific innate immunity means that it may provide a twopronged attack against tumour cells whilst sparing normal tissue

SCREENING OF POTENTIAL PROBIOTIC LACTOBACILLUS STRAINS ISOLATED FROM FERMENTED FOODS, FRUITS AND OF HUMAN ORIGIN

Objective: To screen and characterize Lactobacillus strains having potential probiotic properties from fermented foods and fruits, and to investigate cell surface characteristics and antimicrobial activity against food-borne and gastrointestinal tract (GIT) pathogens.Methods and Results: In the present study, twenty five Lactobacillus strains were isolated from fruits, fermented foods and human origin on De Man Rogosa and Sharpe (MRS) agar plates and identified on the basis of their phenotypic characteristics and 16s rDNA sequencing. Isolated Lactobacillus strains tolerated inhibitory substances like bile (upto 4%), NaCl (upto 8%), phenol (upto 0.6%) and low pH (2.0). Six of the isolates exhibited inhibitory activity against food-borne and GIT pathogens by well diffusion method. The isolates appeared to possess hydrophilic cell surface as determined by microbial adhesion to n-hexadecane. Isolates auto-aggregated and also co-aggragated with pathogens tested. The isolates were not susceptible to antibiotics like vancomycin, tobramycin, kanamycin and norfloxacin while were highly susceptible to chloramphenicol, clindamycin, erythromycin, oleandomycin and penicillin G. None of the isolates showed haemolytic activity.Conclusion: Six strains (Lactobacillus paracasei HML1, L. paracasei CR7, L. plantarum BRMV1, L. plantarum F1 and L. plantarum OC6) showed potential probiotic properties as well as strong in vitro antibacterial activity against various food-borne and gastrointestinal tract (GIT) pathogens.  Keywords: Antimicrobial activity, Lactobacillus, Acid tolerance, Bile tolerance, Hydrophobicity, ProbioticsÂ

The Kenya UK Breast Cancer Awareness Week: curriculum codesign and codelivery with direct and lived experience of breast cancer diagnosis and management

Global health education holds a paradox: the provision of global health degrees focusing on challenges in low-income and middle-income countries has increased in high-income countries, while those in these low-income and middle-income countries lack access to contribute their expertise, creating an ‘information problem’. Breast cancer is a pressing global health priority, which requires curriculum design, implementation, ownership and leadership by those with direct and lived experience of breast cancer. The Kenya-UK Breast Cancer Awareness Week was conceptualised following the signing of the Memorandum of Understanding between the Kenyan and UK governments launching the Kenya UK Health Alliance. This alliance aims to promote health cooperation to address Kenya’s breast cancer challenge. Here, we present the first of the collaborative’s initiatives: a breast cancer global health education programme designed, implemented, owned and led by Kenyan stakeholders. We present the utilisation of the Virtual Roundtable for Collaborative Education Design for the design and implementation of a nationwide virtual breast cancer awareness week delivered across eleven Kenyan medical schools. By involving partners with lived and/or professional experience of breast cancer in Kenya in all stages of the design and delivery of the awareness week, the project experimented with disrupting power dynamics and fostered ownership of the initiative by colleagues with direct expertise of breast cancer in Kenya. This initiative provides a platform, precedent and playbook to guide professionals from other specialties in the design and implementation of similar global collaborative ventures. We have used this approach to continue to advocate for global health curricula design change, so that those with lived experiences of global health challenges in their contextualised professional and personal environments are given leadership, reward and ownership of their curricula and further to highlight breast cancer as a global heath priority

Explainable AI (XAI): core ideas, techniques and solutions

As our dependence on intelligent machines continues to grow, so does the demand for more transparent and interpretable models. In addition, the ability to explain the model generally is now the gold standard for building trust and deployment of Artificial Intelligence (AI) systems in critical domains. Explainable Artificial Intelligence (XAI) aims to provide a suite of machine learning (ML) techniques that enable human users to understand, appropriately trust, and produce more explainable models. Selecting an appropriate approach for building an XAI-enabled application requires a clear understanding of the core ideas within XAI and the associated programming frameworks. We survey state-of-the-art programming techniques for XAI and present the different phases of XAI in a typical ML development process. We classify the various XAI approaches and using this taxonomy, discuss the key differences among the existing XAI techniques. Furthermore, concrete examples are used to describe these techniques that are mapped to programming frameworks and software toolkits. It is the intention that this survey will help stakeholders in selecting the appropriate approaches, programming frameworks, and software toolkits by comparing them through the lens of the presented taxonomy

Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs

BackgroundLevetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness.ObjectivesTo compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim®, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy.DesignTwo pragmatic randomised unblinded non-inferiority trials run in parallel.SettingOutpatient services in NHS hospitals throughout the UK.ParticipantsThose aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication.InterventionsParticipants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program.Main outcome measuresThe primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness.ResultsFocal epilepsy. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. Generalised and unclassifiable epilepsy. Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective.LimitationsThe SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions.Future workSANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel.ConclusionsFocal epilepsy - The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. Generalised and unclassifiable epilepsy - The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate.Trial registrationCurrent Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 75. See the NIHR Journals Library website for further project information