Cancer immune surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognized by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumor cells by expressing death ligand cytokines of the tumor necrosis factor ligand family. However, some tumor cells can escape immune elimination and progress. Acquisition of resistance to the death ligand-induced apoptotic pathway can be obtained through cleavage of effector cell expressed death ligands into a poorly active form, mutations or silencing of the death receptors, or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/dysfunctional death ligand signaling curbs its cytotoxicity. Moreover, DRs can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signaling does not only give a passive resistance against cell death but actively drives tumor cell motility, invasion, and contributes to consequent metastasis. This dual contribution of the death receptor signaling in both the early, elimination phase, and then in the late, escape phase of the tumor immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumor-eliminating immune effector function even in the absence of activation of the immune system against the tumor. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.
Acute myeloid leukaemia (AML) is an aggressive cancer with 50–75% of patients relapsing even after successful chemotherapy. The role of the bone marrow microenvironment (BMM) in protecting AML cells from chemotherapeutics and causing consequent relapse is increasingly recognised. However the role that the anti-apoptotic Bcl-2 proteins play as effectors of BMM-mediated drug resistance are less understood. Here we show that bone marrow mesenchymal stromal cells (BMSC) provide resistance to AML cells against BH3-mimetics, cytarabine and daunorubicin, but this is not mediated by Bcl-2 and/or Bcl-XL as previously thought. Instead, BMSCs induced Mcl-1 expression over Bcl-2 and/or Bcl-XL in AML cells and inhibition of Mcl-1 with a small-molecule inhibitor, A1210477, or repressing its expression with the CDC7/CDK9 dual-inhibitor, PHA-767491 restored sensitivity to BH3-mimetics. Furthermore, combined inhibition of Bcl-2/Bcl-XL and Mcl-1 could revert BMSC-mediated resistance against cytarabine + daunorubicin. Importantly, the CD34+/CD38− leukemic stem cell-encompassing population was equally sensitive to the combination of PHA-767491 and ABT-737. These results indicate that Bcl-2/Bcl-XL and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival.
Three pilot-scale, horizontal-flow biofilm reactors (HFBRs 1-3) were used to treat methane (CH 4 )-contaminated air to assess the potential of this technology to manage emissions from agricultural activities, waste and wastewater treatment facilities, and landfills. The study was conducted over two phases (Phase 1, lasting 90 days and Phase 2, lasting 45 days). The reactors were operated at 10 C (typical of ambient air and wastewater temperatures in northern Europe), and were simultaneously dosed with CH 4 -contaminated air and a synthetic wastewater (SWW). The influent loading rates to the reactors were 8.6 g CH 4 /m 3 /hr (4.3 g CH 4 /m 2 TPSA/hr; where TPSA is top plan surface area). Despite the low operating temperatures, an overall average removal of 4.63 g CH 4 /m 3 /day was observed during Phase 2. The maximum removal efficiency (RE) for the trial was 88%. Potential (maximum) rates of methane oxidation were measured and indicated that biofilm samples taken from various regions in the HFBRs had mostly equal CH 4 removal potential. In situ activity rates were dependent on which part of the reactor samples were obtained. The results indicate the potential of the HFBR, a simple and robust technology, to biologically treat CH 4 emissions. Implications:The results of this study indicate that the HFBR technology could be effectively applied to the reduction of greenhouse gas emissions from wastewater treatment plants and agricultural facilities at lower temperatures common to northern Europe. This could reduce the carbon footprint of waste treatment and agricultural livestock facilities. Activity tests indicate that methanotrophic communities can be supported at these temperatures. Furthermore, these data can lead to improved reactor design and optimization by allowing conditions to be engineered to allow for improved removal rates, particularly at lower temperatures. The technology is simple to construct and operate, and with some optimization of the liquid phase to improve mass transfer, the HFBR represents a viable, cost-effective solution for these emissions.
Background Proton pump inhibitors (PPIs) are one of the most frequently prescribed drug classes in the older person. Indications for PPI use are outlined in the NICE guidelines, however they are often prescribed without an appropriate indication resulting in increased healthcare costs and increased exposure to potential adverse clinical effects. Methods To determine the rate of inappropriate prescribing of PPI’s, an audit was carried out to assess the incidence of inappropriate prescribing in an Acute Rehabilitation facility pre and post Education to Hospital Doctors. An audit was carried out, pre and post intervention, on patients over the age of 65 years admitted to an acute rehabilitation hospital between 2018 and 2019. Patient’s medical charts were reviewed and data was collected on PPI prescribing. Results Cycle 1-Pre Education; 83 people included in the audit. Mean age was 80.8 years[SD ±9]. 43% of patients were on a PPI, all of which were prescribed the generic form. 83.4% of patients had no indication for PPI use. Of the 16.6%, indications included GORD, Barrett’s oesophagus, PUD and PPI prophylaxis against NSAID’s including aspirin. 77.7% were on therapeutic dose without any indication. 100% of patients were on PPI for longer than 6 weeks. Cycle 2, Post education: 86 patients were included in re-audit. Mean age was 81.5[SD ±10]. 60.4% of patients were on PPI. Of those, 55% had no indication for PPI. Of the 44% on PPI, indications were similar to those in Cycle 1. 83% of patients were on PPI longer than 6 weeks. 56.5% were on inappropriate dose of PPI. Conclusion This audit highlighted the inappropriate prescribing of PPI’s in the older person. By providing education to Doctors about NICE PPI prescribing guidelines, overall rate of inappropriate prescribing of PPI decreased by 28.4% and accurate dosing of PPI improved by 21.2%.
Background Statins are frequently prescribed in older patients for prevention of cardiovascular disease and treatment of hypercholesterolemia. However, there is little evidence to indicate that statins have any benefit in older patients with life expectancy less than 10 years and of those patients in long term care whose average life expectancy is approximately 3-5 years. In addition, statins are associated with significant adverse side effects and contribute to the burden of polypharmacy in older patients. Methods Patients residing in a long term care facility were reviewed and data was collected from their medical notes and medication records in order to; (1) Quantify the proportion of patients on statin therapy (2) Review the indication for statin therapy (3) Investigate the inappropriate prescribing of statins in nursing home patients. Results 55 patients were included in the study. Of the 55 patients, 7 [12.7%] patients were on a statin. Average age of patients on a statin was 77.8 years[SD 9.4]. Of the 7 patients, 2 were on a statin for primary prevention and 5 patients were on for secondary prevention. Average cholesterol in primary prevention group was 3.3mmol/L, average LDL was 1.3 mmol/L. Of the 7 patients on statin for secondary prevention, indications included ischaemic stroke[n= 4] and ischaemic heart disease [n=3]. Average Total cholesterol in secondary prevention group was 3.8 mmol/L and average LDL was 1.91 mmol/L. The average Rockwood Clinical Frailty Scale Score of the patients on statin therapy was 7. Conclusion Firstly, this study highlights the incidence of inappropriate prescribing of statins for primary prevention in frail older patients in long term care. It also raises the question surrounding the indication of statin therapy in secondary prevention where cholesterol level are within target range highlighting the need for further studies examining the benefit of statins in frail older patients in LTC.
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