Practical multimodal care for cancer cachexia

PURPOSE OF REVIEW: Cancer cachexia is common and reduces function, treatment tolerability and quality of life. Given its multifaceted pathophysiology a multimodal approach to cachexia management is advocated for, but can be difficult to realise in practice. We use a case-based approach to highlight practical approaches to the multimodal management of cachexia for patients across the cancer trajectory. RECENT FINDINGS: Four cases with lung cancer spanning surgical resection, radical chemoradiotherapy, palliative chemotherapy and no anticancer treatment are presented. We propose multimodal care approaches that incorporate nutritional support, exercise, and anti-inflammatory agents, on a background of personalized oncology care and family-centred education. Collectively, the cases reveal that multimodal care is part of everyone's remit, often focuses on supported self-management, and demands buy-in from the patient and their family. Once operationalized, multimodal care approaches can be tested pragmatically, including alongside emerging pharmacological cachexia treatments. SUMMARY: We demonstrate that multimodal care for cancer cachexia can be achieved using simple treatments and without a dedicated team of specialists. The sharing of advice between health professionals can help build collective confidence and expertise, moving towards a position in which every team member feels they can contribute towards multimodal care

Practical multimodal care for cancer cachexia

Purpose of reviewCancer cachexia is common and reduces function, treatment tolerability and quality of life. Given its multifaceted pathophysiology a multimodal approach to cachexia management is advocated for, but can be difficult to realise in practice. We use a case-based approach to highlight practical approaches to the multimodal management of cachexia for patients across the cancer trajectory.Recent findingsFour cases with lung cancer spanning surgical resection, radical chemoradiotherapy, palliative chemotherapy and no anticancer treatment are presented. We propose multimodal care approaches that incorporate nutritional support, exercise, and anti-inflammatory agents, on a background of personalized oncology care and family-centred education. Collectively, the cases reveal that multimodal care is part of everyone's remit, often focuses on supported self-management, and demands buy-in from the patient and their family. Once operationalized, multimodal care approaches can be tested pragmatically, including alongside emerging pharmacological cachexia treatments.SummaryWe demonstrate that multimodal care for cancer cachexia can be achieved using simple treatments and without a dedicated team of specialists. The sharing of advice between health professionals can help build collective confidence and expertise, moving towards a position in which every team member feels they can contribute towards multimodal care

Anomalous relaxation kinetics of biological lattice-ligand binding models

We discuss theoretical models for the cooperative binding dynamics of ligands to substrates, such as dimeric motor proteins to microtubules or more extended macromolecules like tropomyosin to actin filaments. We study the effects of steric constraints, size of ligands, binding rates and interaction between neighboring proteins on the binding dynamics and binding stoichiometry. Starting from an empty lattice the binding dynamics goes, quite generally, through several stages. The first stage represents fast initial binding closely resembling the physics of random sequential adsorption processes. Typically this initial process leaves the system in a metastable locked state with many small gaps between blocks of bound molecules. In a second stage the gaps annihilate slowly as the ligands detach and reattach. This results in an algebraic decay of the gap concentration and interesting scaling behavior. Upon identifying the gaps with particles we show that the dynamics in this regime can be explained by mapping it onto various reaction-diffusion models. The final approach to equilibrium shows some interesting dynamic scaling properties. We also discuss the effect of cooperativity on the equilibrium stoichiometry, and their consequences for the interpretation of biochemical and image reconstruction results.Comment: REVTeX, 20 pages, 17 figures; review, to appear in Chemical Physics; v2: minor correction

Reflections on Navigating a Pandemic: Perspectives from the Chemical Biology Community

The early-career researchers showcased in this ChemBioTalents special collection, and many others who have established their independent scientific careers over the last three years, have experienced a unique set of circumstances. The Covid-19 pandemic necessitated new forms of communication and interpersonal interactions: From online interviews and virtual networking to relocating and establishing labs during a pandemic, we faced many challenges, but also unexpected opportunities. In this perspective, we reflect on this unique and formative time through personal anecdotes and viewpoints, trying to capture diverse experiences from the Chemical Biology community and beyond. We have tried to get a broad and varied set of perspectives, however, the selection is biased towards researchers who were able to start their independent careers.1

Semienzymatic cyclization of disulfide-rich peptides using sortase A

Background: Sortase A (SrtA) is a transpeptidase capable of catalyzing the formation of amide bonds. Results: SrtA was used to backbone-cyclize disulfide-rich peptides, including kalata B1, -conotoxin Vc1.1, and SFTI-1. Conclusion: SrtA-mediated cyclization is applicable to small disulfide-rich peptides. Significance: SrtA-mediated cyclization is an alternative to native chemical ligation for the cyclization of small peptides of therapeutic interest

Ambient air quality and human health in India

700 million Indians have used solid fuels in their homes for the last 30 years, contributing substantially to air pollutant emissions. The Indian economy and industrial, power generation, and transport sectors have grown considerably over the last decade, increasing emissions of air pollutants. These air pollutant emissions have caused present-day concentrations of ambient PM2.5 and O3 in India to be amongst the highest in the world. Exposure to this air pollution is the second leading risk factor in India, contributing one-quarter of the global disease burden attributable to air pollution exposure. Air pollutant emissions are predicted to grow extensively over the coming years in India. Despite the importance of air quality in India, it remains relatively understudied, and knowledge of the sources and processes causing air pollution is limited. This thesis aims to understand the contribution of different pollution sources to the attributable disease burden from ambient air pollution exposure in India and the effects of future air pollution control pathways. The attributable disease burden from ambient PM2.5 exposure in India is substantial, where large reductions in emissions will be required to reduce the health burden due to the non-linear exposure-response relationship. The attributable disease burden from ambient O3 exposure is larger than previously thought and is of similar magnitude to that from PM2.5 in the future. Key sources contributing to the present day disease burden from ambient PM2.5 and O3 exposure are the emissions from the residential combustion of solid fuels, land transport, and coal combustion in power plants. The attributable disease burden is estimated to increase in the future due to population ageing and growth. Stringent air pollution control pathways are required to provide critical public health benefits in India in a challenging environment. A key focus should be to reduce the combustion of solid fuels

Role of Acetaldehyde in Ethanol Reversal of Tolerance to Morphine-Induced Respiratory Depression in Mice

BACKGROUND: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression. METHODS: Tolerance was induced in mice by 6-days implantation of a 75 mg morphine pellet with control mice implanted with a placebo pellet. Tolerance was assessed by acute morphine administration on day 6 and respiration measured by plethysmography. Levels of acetaldehyde were inhibited or enhanced by pre-treatments with the acetaldehyde chelator D-penicillamine and the inhibitor of acetaldehyde dehydrogenase disulfiram respectively. RESULTS: Morphine pellet implanted mice displayed tolerance to an acute dose of morphine compared to placebo pellet implanted controls. Acute acetaldehyde administration dose-dependently reversed tolerance to morphine respiratory depression. As previously demonstrated, ethanol reversed morphine tolerance, and this was inhibited by D-penicillamine pre-treatment. An acute, low dose of ethanol that did not significantly reverse morphine tolerance was able to do so following disulfiram pre-treatment. CONCLUSION: These data suggest that acetaldehyde, the primary metabolite of ethanol, is responsible for the reversal of morphine tolerance observed following ethanol administration

Assessment of Target Volume and Organ at Risk Contouring Variability within the Context of UK Head and Neck and Lung Cancer Radiotherapy Clinical Trials

AIMS: Radiotherapy quality assurance (RTQA) is now a requirement of radiotherapy trials since poor target volume and organ at risk (OAR) contouring has been shown to impact on patient outcomes within the context of clinical trials. The first hypothesis for this research is that statistically significant inter-observer variation exists amongst clinical oncologists’ target volume and OAR contours within the context of the pre-trial quality assurance (QA) benchmark cases for four different UK radiotherapy trials. The second hypothesis is directed towards confirming that RTQA feedback during the pre-trial benchmark period does influence contouring for head and neck cancers. MATERIALS/METHODS: Four radiotherapy trials (ART-DECO, COSTAR, IDEAL and i-START trials) that require all prospective investigators to submit pre-accrual benchmark cases were selected. All benchmark cases until November 2012 were collected in DICOM format. The investigator contours were grouped into either target contours (TARGET) i.e. CTV1, parallel OARs (OAR-P) i.e. parotid glands, lungs and heart or serial OARs (OAR-S) i.e. brainstem, spinal cord and oesophagus. These were then analysed using a tumour management group (TMG) consensus contour to determine whether statistically significant differences existed between them. The local conformity index (L-CI) for each structure was also calculated for analysis. RESULTS: Analysis of the pre-trial benchmark cases revealed statistically significant differences (p=<0.05) between clinical oncologists’ target volume, serial and parallel OAR contours. Analysis of the resubmitted head and neck pre-trial benchmark cases also revealed statistically significant differences between first and subsequent submission contours. CONCLUSIONS: This research revealed that a statistically significant difference does exist in clinical oncologists’ target volume and OAR contours within the pre-trial QA benchmark cases for both lung and head and neck cancers. It was also revealed that RTQA feedback during the pre-trial benchmark period had a positive and statistically significant impact on head and neck clinician contouring

Synthesis and evaluation of novel inhibitors of 1-Deoxy-D-xylolose-5-phosphate reductoisomerase as potential antimalarials

Malaria continues to be an enormous health-threat in the developing world and the emergence of drug resistance has further compounded the problem. The parasite-specific enzyme, 1-deoxY-D-xylulose-S-phosphate reductoisomerase (DXR), has recently been validated as a promising antimalarial drug target. The present study comprises a combination of synthetic, physical organic, computer modelling and bioassay techniques directed towards the development of novel DXR inhibitors. A range of 2-heteroarylamino-2-oxoethyl- and 2- heteroarylamino-2-oxopropyl phosphonate esters and their corresponding phosphonic acid salts have been synthesised as analogues of the highly active DXR inhibitor, fosmidomycin. Treatment of the heteroarylamino precursors with chloroacetyl chloride or chloropropionyl chloride afforded chloroamide intermediates, Arbuzov reactions of which led to the corresponding diethyl phosphonate esters. Hydrolysis of the esters has been effected using bromotrimethylsilane. Twenty-four new compounds have been prepared and fully characterised using elemental (HRMS or combustion) and spectroscopic (1- and 2-D NMR and IR) analysis. A 31p NMR kinetic study has been carried out on the two-step silylation reaction involved in the hydrolysis of the phosphonate esters and has provided activation parameters for the reaction. The kinetic analysis was refined using a computational method to give an improved fit with the experimental data. Saturation transfer difference (STD) NMR analysis, computer-simulated docking and enzyme inhibition assays have been used to evaluate the enzyme-binding and -inhibition potential of the synthesised ligands. Minimal to moderate inhibitory activity has been observed and several structure-activity relationships have been identified. In silica exploration of the DXR active site has revealed an additional binding pocket and information on the topology of the active site has led to the de novo design of a new series of potential ligands.KMBT_363Adobe Acrobat 9.54 Paper Capture Plug-i