Hypothalamic GABAergic neurons expressing Cellular Retinoic Acid Binding Protein 1 (CRABP1) are sensitive to metabolic status and liraglutide in male mice.

INTRODUCTION: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing Cellular retinoic acid binding protein 1 (Crabp1). METHODS: Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of Crabp1 across the mouse brain and characterized the molecular identity of Crabp1ARC neurons. We also determined whether Crabp1ARC neurons are sensitive to fasting, leptin and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity. RESULTS: Crabp1ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and distinct from the prototypical melanocortin neurons. Crabp1ARC neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing Htr3b, Tbx19 and Tmem215, respectively. Notably, Crabp1ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism. CONCLUSION: Crabp1ARC neurons represent a novel heterogenous population of GABAergic neurons sensitive to metabolic status.

Improving the management of open tibia fractures, Malawi.

Objective: To assess the impact of an open fracture intervention bundle on clinical management and patient outcomes of adults in Malawi with open tibia fractures. Methods: We conducted a before-and-after implementation study in Malawi in 2021 and 2022 to assess the impact of an open fracture intervention bundle, including a national education course for clinical officers and management guidelines for open fractures. We recruited 287 patients with open tibia fractures. The primary outcome was a before-and-after comparison of the self-reported short musculoskeletal function assessment score, a measure of patient function. Secondary outcomes included clinical management; and clinician knowledge and implementation evaluation outcomes of 57 health-care providers attending the course. We also constructed multilevel regression models to investigate associations between clinical knowledge, patient function, and implementation evaluation before and after the intervention. Findings: The median patient function score at 1 year was 6.8 (interquartile range, IQR: 1.5 to 14.5) before intervention and 8.4 (IQR: 3.8 to 23.2) after intervention. Compared with baseline scores, we found clinicians' open fracture knowledge scores improved 1 year after the intervention was implemented (mean posterior difference: 1.6, 95% highest density interval: 0.9 to 2.4). However, we found no difference in most aspects of clinicians' open fracture management practice. Conclusion: Despite possible improvement in clinician knowledge and positive evaluation of the intervention implementation, our study showed that there was no overall improvement in clinical management, and weak evidence of worsening patient function 1 year after injury, after implementation of the open fracture intervention bundle.

Factors Influencing Recovery From Pediatric Stroke Based on Discussions From a UK-Based Online Stroke Community: Qualitative Thematic Study.

BACKGROUND: The incidence of stroke in children is low, and pediatric stroke rehabilitation services are less developed than adult ones. Survivors of pediatric stroke have a long poststroke life expectancy and therefore have the potential to experience impairments from their stroke for many years. However, there are relatively few studies characterizing these impairments and what factors facilitate or counteract recovery. OBJECTIVE: This study aims to characterize the main barriers to and facilitators of recovery from pediatric stroke. A secondary aim was to explore whether these factors last into adulthood, whether they change, or if new factors impacting recovery emerge in adulthood. METHODS: We performed a qualitative thematic analysis based on posts from a population of participants from a UK-based online stroke community, active between 2004 and 2011. The analysis focused on users who talked about their experiences with pediatric stroke, as identified by a previous study. The posts were read by 3 authors, and factors influencing recovery from pediatric stroke were mapped into 4 areas: medical, physical, emotional, and social. Factors influencing recovery were divided into short-term and long-term factors. RESULTS: There were 425 posts relating to 52 survivors of pediatric stroke. Some survivors of stroke posted for themselves, while others were talked about by a third party (mostly parents; 31/35, 89% mothers). In total, 79% (41/52) of survivors of stroke were aged ≤18 years and 21% (11/52) were aged >18 years at the time of posting. Medical factors included comorbidities as a barrier to recovery. Medical interventions, such as speech and language therapy and physiotherapy, were also deemed useful. Exercise, particularly swimming, was deemed a facilitator. Among physical factors, fatigue and chronic pain could persist decades after a stroke, with both reported as a barrier to feeling fully recovered. Tiredness could worsen existing stroke-related impairments. Other long-standing impairments were memory loss, confusion, and dizziness. Among emotional factors, fear and uncertainty were short-term barriers, while positivity was a major facilitator in both short- and long-term recovery. Anxiety, grief, and behavioral problems hindered recovery. The social barriers were loneliness, exclusion, and hidden disabilities not being acknowledged by third parties. A good support network and third-party support facilitated recovery. Educational services were important in reintegrating survivors into society. Participants reported that worrying about losing financial support, such as disability allowances, and difficulties in obtaining travel insurance and driving licenses impacted recovery. CONCLUSIONS: The lived experience of survivors of pediatric stroke includes long-term hidden disabilities and barriers to rehabilitation. These are present in different settings, such as health care, schools, workplaces, and driving centers. Greater awareness of these issues by relevant professional groups may help ameliorate them.

Epidemiology and Treatment of Distal Radius Fractures at Four Public Hospitals in Malawi.

BACKGROUND: Little is known about the burden or management of distal radius fractures (DRFs) in low- and middle-income countries. The purpose of this study was to describe the care of DRFs in Malawi. METHODS: We retrospectively reviewed a registry of all patients with fractures who presented to the orthopaedic departments at four public hospitals in Malawi. RESULTS: Totally, 1,440 patients (14.5%) were with a DRF. Average age was 40, and 888 (62.0%) were male. Surgery was done for 122 patients (9.5%). Patients presenting to Queen Elizabeth Hospital, patients presenting after a fall, and patients initially evaluated by an orthopaedic registrar or orthopaedic clinical officer had lower odds of receiving surgical treatment. Meanwhile, open injuries had the greatest odds of receiving surgery. CONCLUSION: The most common musculoskeletal injury among patients in the Malawi Fracture Registry was fractures of the distal radius. These most affected young adult male patients may benefit from surgery; however, the majority were managed nonsurgically. Lack of access to surgical fixation and conservative follow-up may have long-term functional consequences in a predominantly agrarian society. Outcomes-based research is needed to help guide management decisions and standardize patient care and referral protocols.

Visualization of translation reorganization upon persistent ribosome collision stress in mammalian cells.

Aberrantly slow ribosomes incur collisions, a sentinel of stress that triggers quality control, signaling, and translation attenuation. Although each collision response has been studied in isolation, the net consequences of their collective actions in reshaping translation in cells is poorly understood. Here, we apply cryoelectron tomography to visualize the translation machinery in mammalian cells during persistent collision stress. We find that polysomes are compressed, with up to 30% of ribosomes in helical polysomes or collided disomes, some of which are bound to the stress effector GCN1. The native collision interface extends beyond the in vitro-characterized 40S and includes the L1 stalk and eEF2, possibly contributing to translocation inhibition. The accumulation of unresolved tRNA-bound 80S and 60S and aberrant 40S configurations identifies potentially limiting steps in collision responses. Our work provides a global view of the translation machinery in response to persistent collisions and a framework for quantitative analysis of translation dynamics in situ.

Screening of probiotic Lactobacillus to reduce peanut allergy and with potential anti-allergic activity.

BACKGROUND: Peanut is a significant source of nutrition and a valuable oilseed crop. It is also a serious allergy source, which poses a threat to 1.1% of the population. This study aimed to screen lactic acid bacteria (LAB) with the capacity to alleviate peanut allergenicity and exhibit anti-allergic properties. RESULT: The results show that LAB can make use of substances in peanuts to reduce the pH of peanut milk from 6.603 to 3.593-4.500 by acid production and that it can utilize the protein in peanuts to reduce the allergenic content (especially Ara h 1) and improve biological activity in peanut pulp. The content of Ara h 1 peanut-sensitizing protein was reduced by 74.65% after fermentation. The protein extracted from fermented peanut pulp is more readily digestible by gastrointestinal juices. The inhibitory activity assay of hyaluronidase (an enzyme with strong correlation to allergy) increased from 46.65% to a maximum of 90.57% to reveal that LAB fermentation of peanut pulp exhibited a robust anti-allergic response. CONCLUSION: The strains identified in this study exhibited the ability to mitigate peanut allergenicity partially and to possess potential anti-allergic properties. Lactobacillus plantarum P1 and Lactobacillus salivarius C24 were identified as the most promising strains and were selected for further research. © 2023 Society of Chemical Industry.

Is human immunodeficiency virus a risk factor for the development of nonunion?-a case-control study.

Objective: Human immunodeficiency virus (HIV) infection has been suggested to be associated with an increased risk of the development of nonunion after a fracture. This prospective matched case-control study in South Africa investigated common risk factors, including HIV status, that influence the development of a nonunion after a femur or tibia fracture. Methods: Adult participants (cases) with established nonunions of the femur or tibia shaft were recruited over a 16-month period, between December 2017 and April 2019. They were matched for (1) age; (2) sex; (3) fracture site; and (4) fracture management type, with "control" participants who progressed to fracture union within 6 months of injury. All participants were tested for HIV. Multivariable logistic regression models were constructed to investigate associations between known risk factors for the development of nonunion and impaired fracture healing. Results: A total of 57 cases were matched with 57 "control" participants (44/57 male, 77.2% vs. 13/57 female, 22.8%, median age 36 years). HIV status was not associated with the development of nonunion after the management of tibia and femur fractures, on both univariate (odds ratio, 0.40; confidence interval, 0.10-1.32; P = 0.151) or multivariable (odds ratio, 0.86; confidence interval, 0.18-3.73; P = 0.831) analysis. No other confounding factors were shown to have any statistically significant impact on the odds of developing nonunion in this study cohort. Conclusion: This study demonstrates that HIV does not seem to increase the risk of the development of nonunion and HIV-positive individuals who sustain a fracture can be managed in the same manner as those who are HIV negative.

New formulations of fermented milk drinks with fruit pulp added: Physicochemical characteristics during storage and nutritional profile

The aim of this study was to evaluate the nutritional profile and the physicochemical characteristics during storage of newly developed formulations of fermented milk drinks with added pineapple, mango and passion fruit pulp. The fermented drinks showed a high content of protein, iron, and calcium. The passion fruit milk drink had the lowest pH (4.13) and highest acidity (0.95%, expressed in % of lactic acid), which was significantly different (p<0.05) from the pineapple and mango drinks. As for syneresis and sedimentation, the pineapple milk drink had the highest rates at 14 days storage, with 34.33% and 6.50%, respectively and was significantly different (p≤0.05) when compared to the mango and passion fruit milk drinks. In conclusion, newly developed fermented milk drinks with added fruit pulp were a source of several nutrients. We observed physical-chemical characteristics suitable for a fermented milk product during storage.

El objetivo de este estudio fue el desarrollo de nuevas formulaciones de bebidas lácteas fermentadas adicionadas de piña, mango y maracuyá, para evaluar el perfil nutricional y las características fisicoquímicas durante el almacenamiento. Las bebidas fermentadas mostraron un alto contenido en proteínas, hierro y calcio. En cuanto a las características fisicoquímicas durante el almacenamiento, la bebida láctea de maracuyá presentó el pH más bajo (4,13) y la acidez más alta (0,95%, expresada en % de ácido láctico), con una diferencia significativa (p < 0,05), en comparación con las bebidas de piña y mango. En cuanto a sinéresis y sedimentación, la bebida láctea de piña presentó los mayores índices a los 14 días de almacenamiento, con 34,33% y 6,50%, respectivamente, y con diferencia significativa (p ≤ 0,05) al compararla con las bebidas lácteas de mango y maracuyá. En conclusión, las bebidas lácteas fermentadas con adición de pulpa de fruta son una fuente de varios nutrientes, y de características físico-químicas adecuadas para un producto lácteo fermentado durante el almacenamiento.

Functional outcomes and quality of life at 1-year follow-up after an open tibia fracture in Malawi: a multicentre, prospective cohort study.

BACKGROUND: Injuries are a major cause of disability globally and injury incidence is rapidly increasing, largely due to road traffic injuries in low-income and middle-income countries. Current estimates of the scale and consequences of disability from injury are largely based on modelling studies, with a scarcity of empirical evidence from severe injuries in low-income countries. We aimed to better understand the outcomes for individuals with open tibia fractures in Malawi. METHODS: In this multicentre, prospective cohort study, adults (aged ≥18 years) with open tibia fractures were systematically recruited at six hospitals in Malawi (two tertiary hospitals and four district hospitals). Follow-up lasted at least 1 year, during which in-person follow-up reviews were done at 6 weeks, 3 months, 6 months, and 1 year post-injury. The primary outcome was function at 1 year post-injury, measured by the Short Musculoskeletal Functional Assessment (SMFA) score. Secondary outcomes included quality-adjusted life-years (QALYs; as determined via the European Quality of Life 5-Dimensions 3-Levels [EQ-5D-3L] survey) and fracture-related infection at 1 year post-injury. Multilevel regression models investigated associations between SMFA score, EQ-5D-3L, baseline factors, and orthopaedic management. FINDINGS: Between Feb 12, 2021, and March 14, 2022, 287 participants were enrolled (median age 34 years [IQR 25-44]; 84% male). The most common mode of injury was road traffic injuries (194 [68%] of 287). Overall, 268 (93%) participants had debridement; of the 63 participants who were debrided in district hospitals, 47 (75%) had the procedure under local or no anaesthesia. Following substantial declines by 6 weeks after injury, function and quality of life had not recovered by 1 year post-injury for participants with Gustilo grade I-II fractures (posterior mean SMFA at 1 year: 10·5, 95% highest density interval [HDI]: 9·5-11·6; QALYs: 0·73, 95% HDI: 0·66-0·80) nor Gustilo grade III fractures (posterior mean SMFA at 1 year: 14·9, 95% HDI: 13·4-16·6; QALYs: 0·67, 95% HDI: 0·59-0·75). For all fracture grades, intramedullary nailing substantially improved function and quality of life at 1 year post-injury. Delayed definitive fixation after 5 days had 5-times greater odds of infection compared with early management within 2 days (adjusted odds ratio: 5·1, 95% CI 1·8-16·1; p=0·02). INTERPRETATION: Adults with open tibia fractures in Malawi have poor function and quality of life in the 1 year following injury. Centralised orthopaedic surgical management, including early definitive fixation and intramedullary nailing for more severe injuries, might improve outcomes. FUNDING: Wellcome Trust. TRANSLATION: For the Chichewa translation of the abstract see Supplementary Materials section.

Training Traditional Bonesetters in Basic Principles of Fracture Treatment: A Proof of Concept in Ghana.

BACKGROUND: Our study assessed the effectiveness of a traditional bonesetter (TBS) educational program that was designed to increase knowledge, reduce complications, and promote the referral of patients to local hospitals by TBSs when necessary. METHODS: From April to December 2021, TBSs from the Northern Sector (the Northern, Savannah, and North East regions) and the Ashanti region of Ghana underwent a 4-day training course that had been designed to teach basic principles of fracture care with the use of local tools. We assessed the levels of knowledge of the TBSs both before and after training. The change in practice of the trained TBSs also was assessed at 6 months using a structured questionnaire and a checklist. RESULTS: In total, 157 TBSs were trained in 5 training sessions over a 9-month period. There was an improvement in knowledge in all of the modules of training, with an overall knowledge gain of 19.7% (from 67.2% to 86.9%). At 6 months of follow-up, the practices of TBSs that had most improved were record-keeping, hand hygiene, and patient rehabilitation. As a result of the referral system that was established by the training project, a total of 37 patients were referred to local hospitals in the 6 months following the training. CONCLUSIONS: Formal training for TBSs that was provided by a multidisciplinary team with use of a locally developed curriculum and tools was effective in improving the practice and outcomes of treatment by TBSs. There was marked knowledge retention by the trained TBSs at 6 months after training in fracture management. CLINICAL RELEVANCE: Education, training, and the establishment of referral pathways between TBSs and local hospitals could improve trauma care in Ghana.

Glycosylation and charge distribution orchestrates the conformational ensembles of a biotechnologically promissory phytase in different pHs - a computational study.

Phytases [myo-inositol(1,2,3,4,5,6) hexakisphosphate phosphohydrolases] are phytate-specific phosphatases not present in monogastric animals. Nevertheless, they are an essential supplement to feeding such animals and for human special diets. It is crucial, hence, the biotechnological use of phytases with intrinsic stability and activity at the acid pHs from gastric environments. Here we use Metadynamics (METADY) simulations to probe the conformational space of the Aspergillus nidulans phytase and the differential effects of pH and glycosylation in this same space. The results suggest that strategic combinations of pH and glycosylation affect the stability of native-like conformations and alternate these structures from a metastable to a stable profile. Furthermore, the protein segments previously reported as more thermosensitive in phytases from this family present a pivotal role in the conformational changes at different conditions, especially H2, H5-7, L8, L10, L12, and L17. Also, the glycosylations and the pH-dependent charge balance modulate the mobility and interactions at these same regions, with consequences for the surface solvation and active site exposition. Finally, although the glycosylations have stabilized the native structure and improved the substrate docking at all the studied pHs, the data suggest a higher phytate receptivity at catalytic poses for the unglycosylated structure at pH 6.5 and the glycosylated one at pH 4.5. This behavior agrees with the exact change in optimum pH reported for this enzyme, expressed on low or high glycosylating systems. We hope the results and insights presented here will be helpful in future approaches for rational engineering of technologically promising phytases and intelligent planning of their heterologous expression systems and conditions for use.Communicated by Ramaswamy H. Sarma.

Evaluation of a novel porous antimicrobial media for industrial and HVAC water biocontrol.

A novel treatment method, consisting of pea-gravel with a marine coating supplemented with alkyldimethylbenzylammonium chloride (ADBAC or benzalkonium chloride), has been examined for its antimicrobial performance and coating stability in aqueous environments. Initial column studies examining the porous media's ability to reduce bacterial loads in heating, ventilation, and air conditioning (HVAC) water found average reductions of 94% from pre-flush levels (106 colony forming unit (CFU)/mL) when assessed with R2A spread plates and 83% reductions with SimPlates. There was no observed statistical difference between the average of pre- and post-flush waters from four tests of the media without ADBAC. Taxonomic identification, by 16S rRNA gene sequencing, of colonies drawn from pre- and post-ABDAC R2A plates showed similarities with taxa observed in high frequency from prior cultivation-independent surveys of other cooling tower systems. With this proof of concept, two versions of the media were evaluated for potential coating components released during aqueous exposure. Neither released measurable volatile organic compounds (VOC) components, but one did release bisphenol A and ABDAC compounds. Subsequent column tests of the more durable coating were conducted using cultures of interest in industrial water and demonstrated significant reductions in neutralized post-column Enterococcus faecalis samples and near complete loss of Legionella pneumophila in non-neutralized fluids, but lower reductions in Pseudomonas aeruginosa.

Assessing COVID-19 pandemic policies and behaviours and their economic and educational trade-offs across US states from Jan 1, 2020, to July 31, 2022: an observational analysis.

BACKGROUND: The USA struggled in responding to the COVID-19 pandemic, but not all states struggled equally. Identifying the factors associated with cross-state variation in infection and mortality rates could help to improve responses to this and future pandemics. We sought to answer five key policy-relevant questions regarding the following: 1) what roles social, economic, and racial inequities had in interstate variation in COVID-19 outcomes; 2) whether states with greater health-care and public health capacity had better outcomes; 3) how politics influenced the results; 4) whether states that imposed more policy mandates and sustained them longer had better outcomes; and 5) whether there were trade-offs between a state having fewer cumulative SARS-CoV-2 infections and total COVID-19 deaths and its economic and educational outcomes. METHODS: Data disaggregated by US state were extracted from public databases, including COVID-19 infection and mortality estimates from the Institute for Health Metrics and Evaluation's (IHME) COVID-19 database; Bureau of Economic Analysis data on state gross domestic product (GDP); Federal Reserve economic data on employment rates; National Center for Education Statistics data on student standardised test scores; and US Census Bureau data on race and ethnicity by state. We standardised infection rates for population density and death rates for age and the prevalence of major comorbidities to facilitate comparison of states' successes in mitigating the effects of COVID-19. We regressed these health outcomes on prepandemic state characteristics (such as educational attainment and health spending per capita), policies adopted by states during the pandemic (such as mask mandates and business closures), and population-level behavioural responses (such as vaccine coverage and mobility). We explored potential mechanisms connecting state-level factors to individual-level behaviours using linear regression. We quantified reductions in state GDP, employment, and student test scores during the pandemic to identify policy and behavioural responses associated with these outcomes and to assess trade-offs between these outcomes and COVID-19 outcomes. Significance was defined as p<0·05. FINDINGS: Standardised cumulative COVID-19 death rates for the period from Jan 1, 2020, to July 31, 2022 varied across the USA (national rate 372 deaths per 100 000 population [95% uncertainty interval [UI] 364-379]), with the lowest standardised rates in Hawaii (147 deaths per 100 000 [127-196]) and New Hampshire (215 per 100 000 [183-271]) and the highest in Arizona (581 per 100 000 [509-672]) and Washington, DC (526 per 100 000 [425-631]). A lower poverty rate, higher mean number of years of education, and a greater proportion of people expressing interpersonal trust were statistically associated with lower infection and death rates, and states where larger percentages of the population identify as Black (non-Hispanic) or Hispanic were associated with higher cumulative death rates. Access to quality health care (measured by the IHME's Healthcare Access and Quality Index) was associated with fewer total COVID-19 deaths and SARS-CoV-2 infections, but higher public health spending and more public health personnel per capita were not, at the state level. The political affiliation of the state governor was not associated with lower SARS-CoV-2 infection or COVID-19 death rates, but worse COVID-19 outcomes were associated with the proportion of a state's voters who voted for the 2020 Republican presidential candidate. State governments' uses of protective mandates were associated with lower infection rates, as were mask use, lower mobility, and higher vaccination rate, while vaccination rates were associated with lower death rates. State GDP and student reading test scores were not associated with state COVD-19 policy responses, infection rates, or death rates. Employment, however, had a statistically significant relationship with restaurant closures and greater infections and deaths: on average, 1574 (95% UI 884-7107) additional infections per 10 000 population were associated in states with a one percentage point increase in employment rate. Several policy mandates and protective behaviours were associated with lower fourth-grade mathematics test scores, but our study results did not find a link to state-level estimates of school closures. INTERPRETATION: COVID-19 magnified the polarisation and persistent social, economic, and racial inequities that already existed across US society, but the next pandemic threat need not do the same. US states that mitigated those structural inequalities, deployed science-based interventions such as vaccination and targeted vaccine mandates, and promoted their adoption across society were able to match the best-performing nations in minimising COVID-19 death rates. These findings could contribute to the design and targeting of clinical and policy interventions to facilitate better health outcomes in future crises. FUNDING: Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.

Fear of clowns: An investigation into the aetiology of coulrophobia.

Introduction: Fear of clowns or coulrophobia is a little understood phenomenon despite studies indicating that it has a high prevalence in the general population. There have been no previous investigations into the aetiology of this fear, although several plausible hypotheses from the wider literature can be generated; the fear stems from media portrayals of scary clowns, from the unusual physical appearance or the unpredictable behaviour displayed, or it derives from an unpleasant personal experience. Methods: The current study reviews the literature in this area and also pilots a new questionnaire (Origin of Fear of Clowns Questionnaire; OFCQ) to explore the causes of the fear of clowns in a sample of 528 participants who reported such a fear. Results: Our findings suggest that uncertainty of harmful intent, media influences and unpredictability of behaviour play an important role in the origins of coulrophobia. There are also multiple features of clown appearance which produce a negative experiential state and a sense of a direct threat. Discussion: We conclude that the origins of clown fear are multi-factorial and primarily relate to aspects of their facial appearance, their behaviour, and how they have been portrayed in the media. Surprisingly, fear derived from personal experience was not one of our main findings. Further research is focused on looking at associations between the level of fear and each aetiological category.

Biomarkers for immune checkpoint inhibitors in solid tumors

The use of immune checkpoint inhibitors in solid organ malignancies has become widespread in the last decade. Accumulating evidence shows broad survival benefit as compared to traditional chemotherapies. At the same time, a need has emerged to stratify these drugs in various patient populations and histologies. Consequently, various immune biomarkers have been proposed to help in selecting patients for these therapies. Here, we review the evidence pertaining to biomarkers including programmed death-ligand 1, defective mismatch repair, tumor mutational burden, tumor-infiltrating lymphocytes, gene expression profiles, circulating blood cells, circulating DNA and the gut microbiome. The value of PD-L1 testing in certain malignancies, such as lung and urothelial cancer is highlighted as well as emerging data from trials such as GARNET and CheckMate142 (AU)

Proteome diversification by mRNA translation in cancer.

mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis and is well known to be altered by oncogenes to promote cancer development. This distorted mRNA translation is accompanied by the vulnerability of cancer to inhibitors of key mRNA translation components. Novel studies also suggest that these alternations could be utilized for immunotherapy. Ribosome heterogeneity and alternative responses to nutrient shortages, which aid cancer growth and spread, are proposed to elicit aberrant protein production but may also result in previously unidentified therapeutic targets, such as the presentation of cancer-specific peptides at the surface of cancer cells (neoepitopes). This review will assess the driving forces in tRNA and ribosome function that underlie proteome diversification due to alterations in mRNA translation in cancer cells.