Immunotherapy in Sarcoma: Current Data and Promising Strategies.

Traditionally sarcomas have been considered immunologically quiet tumours, with low tumour mutational burden (TMB) and an immunosuppressive tumour microenvironment (TME), consisting of decreased T-cell infiltration and elevated levels of H1F1α, macrophages and neutrophils.1,2 However, research has shown that a subset of sarcomas are immunologically 'hot' with either high TMB, PDL-1 expression, CD8+ T cells or presence of tertiary lymphoid structures (TLS) demonstrating sensitivity to immunotherapy.3,4 Here, we review the current evidence for immunotherapy use in bone sarcomas (BS) and soft tissue sarcomas (STS), with immune checkpoint inhibitors (ICI) and adoptive cellular therapies including engineered T-cell therapies, chimeric antigen receptor (CAR) T-cell therapies, tumour infiltrating lymphocytes (TILs) and cancer vaccines and biomarkers of response.

Disentangling direct vs indirect effects of microbiome manipulations in a habitat-forming marine holobiont.

Host-associated microbiota are critical for eukaryotic host functioning, to the extent that hosts and their associated microbial communities are often considered "holobionts". Most studies of holobionts have focused on descriptive approaches or have used model systems, usually in the laboratory, to understand host-microbiome interactions. To advance our understanding of host-microbiota interactions and their wider ecological impacts, we need experimental frameworks that can explore causation in non-model hosts, which often have highly diverse microbiota, and in their natural ecological setting (i.e. in the field). We used a dominant habitat-forming seaweed, Hormosira banksii, to explore these issues and to experimentally test host-microbiota interactions in a non-model holobiont. The experimental protocols were aimed at trying to disentangle microbially mediated effects on hosts from direct effects on hosts associated with the methods employed to manipulate host-microbiota. This was done by disrupting the microbiome, either through removal/disruption using a combination of antimicrobial treatments, or additions of specific taxa via inoculations, or a combination of thew two. The experiments were done in mesocosms and in the field. Three different antibiotic treatments were used to disrupt seaweed-associated microbiota to test whether disturbances of microbiota, particularly bacteria, would negatively affect host performance. Responses of bacteria to these disturbances were complex and differed substantially among treatments, with some antibacterial treatments having little discernible effect. However, the temporal sequence of responses antibiotic treatments, changes in bacterial diversity and subsequent decreases in host performance, strongly suggested an effect of the microbiota on host performance in some treatments, as opposed to direct effects of the antibiotics. To further test these effects, we used 16S-rRNA-gene sequencing to identify bacterial taxa that were either correlated, or uncorrelated, with poor host performance following antibiotic treatment. These were then isolated and used in inoculation experiments, independently or in combination with the previously used antibiotic treatments. Negative effects on host performance were strongest where specific microbial antimicrobials treatments were combined with inoculations of strains that were correlated with poor host performance. For these treatments, negative host effects persisted the entire experimental period (12 days), even though treatments were only applied at the beginning of the experiment. Host performance recovered in all other treatments. These experiments provide a framework for exploring causation and disentangling microbially mediated vs. direct effects on hosts for ecologically important, non-model holobionts in the field. This should allow for better predictions of how these systems will respond to, and potentially mitigate, environmental disturbances in their natural context.

Marine protected areas can be useful but are not a silver bullet for kelp conservation.

Kelp forests are among the most valuable ecosystems on Earth, but they are increasingly being degraded and lost due to a range of human-related stressors, leading to recent calls for their improved management and conservation. One of the primary tools to conserve marine species and biodiversity is the establishment of marine protected areas (MPAs). International commitments to protect 30% of the world's ecosystems are gaining momentum, offering a promising avenue to secure kelp forests into the Anthropocene. However, a clear understanding of the efficacy of MPAs for conserving kelp forests in a changing ocean is lacking. In this perspective, we question whether strengthened global protection will create meaningful conservation outcomes for kelp forests. We explore the benefits of MPAs for kelp conservation under a suite of different stressors, focusing on empirical evidence from protected kelp forests. We show that MPAs can be effective against some drivers of kelp loss (e.g., overgrazing, kelp harvesting), particularly when they are maintained in the long-term and enforced as no-take areas. There is also some evidence that MPAs can reduce impacts of climate change through building resilience in multi-stressor situations. However, MPAs also often fail to provide protection against ocean warming, marine heatwaves, coastal darkening, and pollution, which have emerged as dominant drivers of kelp forest loss globally. Although well-enforced MPAs should remain an important tool to protect kelp forests, successful kelp conservation will require implementing an additional suite of management solutions that target these accelerating threats.

Seminoma and dysgerminoma: evidence for alignment of clinical trials and de-escalation of systemic chemotherapy.

Malignant germ cell tumours are a group of rare cancers whose incidence peaks in late adolescence and early adulthood. Dysgerminomas of the ovary and seminomas of the testis are analogous diseases, but seminomas have a 10-fold higher incidence. The two tumours are morphologically identical and are only differentiated by surrounding organ-specific tissue or testicular germ cell neoplasia in situ. They share genetic features including KIT and RAS mutations, amplification of chromosome 12p, and expression of pluripotency markers (NANOG (Nanog homeobox), OCT3/4 (Octamer-binding transcription factor 3/4), and SAL4 (Spalt-like trascription factor 4)). Both histologies are exquisitely sensitive to platinum chemotherapy, and the combination of bleomycin, etoposide, and cisplatin (BEP) yields survival rates greater than 90%. However, BEP causes significant, lifelong toxicity (cardiovascular, renal, respiratory, and neurological) in these young patients with an expectation of cure. Here, we comprehensively review the biological features of dysgerminoma and seminoma to demonstrate that they are biologically analogous diseases. We present available clinical trial data supporting de-escalation of chemotherapy treatment. Finally, we propose that future trials should enrol men, women, and children to benefit all patients regardless of age or sex.

Bad to the Bone: Emerging Approaches to Aggressive Bone Sarcomas.

Bone sarcomas are rare heterogeneous tumors that affect patients of all ages including children, adolescent young adults, and older adults. They include many aggressive subtypes and patient groups with poor outcomes, poor access to clinical trials, and lack of defined standard therapeutic strategies. Conventional chondrosarcoma remains a surgical disease, with no defined role for cytotoxic therapy and no approved targeted systemic therapies. Here, we discuss promising novel targets and strategies undergoing evaluation in clinical trials. Multiagent chemotherapy has greatly improved outcomes for patients with Ewing sarcoma (ES) and osteosarcoma, but management of those with high-risk or recurrent disease remains challenging and controversial. We describe the impact of international collaborative trials, such as the rEECur study, that aim to define optimal treatment strategies for those with recurrent, refractory ES, and evidence for high-dose chemotherapy with stem-cell support. We also discuss current and emerging strategies for other small round cell sarcomas, such as CIC-rearranged, BCOR-rearranged tumors, and the evaluation of emerging novel therapeutics and trial designs that may offer a new paradigm to improve survival in these aggressive tumors with notoriously bad (to the bone) outcomes.

Treatment de-escalation for stage II seminoma.

International Germ Cell Cancer Collaborative Group good-risk metastatic seminoma has cure rates of >95%. Within this risk group, patients with stage II disease exhibit the best oncological outcomes with the standard-of-care treatment strategies of radiotherapy or combination chemotherapy. However, these treatments can be associated with substantial early and late toxic effects. Therapy de-escalation aims to reduce treatment morbidity whilst preserving oncological outcomes. The evidence supporting such approaches is largely from non-randomized institutional data, and therefore this strategy is not recognized as standard of care. Current de-escalation approaches for stage II seminoma include single-agent chemotherapy, radiotherapy and surgery based on early data from clinical studies. Increased recognition of emerging data on treatment modification to reduce morbidity whilst maintaining cure rates and consideration of therapy de-escalation could improve patient survivorship outcomes.

Host genetics, phenotype and geography structure the microbiome of a foundational seaweed.

Interactions between hosts and their microbiota are vital to the functioning and resilience of macro-organisms. Critically, for hosts that play foundational roles in communities, understanding what drives host-microbiota interactions is essential for informing ecosystem restoration and conservation. We investigated the relative influence of host traits and the surrounding environment on microbial communities associated with the foundational seaweed Phyllospora comosa. We quantified 16 morphological and functional phenotypic traits, including host genetics (using 354 single nucleotide polymorphisms) and surface-associated microbial communities (using 16S rRNA gene amplicon sequencing) from 160 individuals sampled from eight sites spanning Phyllospora's entire latitudinal distribution (1,300 km). Combined, these factors explained 54% of the overall variation in Phyllospora's associated microbial community structure, much of which was related to the local environment (~32%). We found that putative "core" microbial taxa (i.e., present on all Phyllospora individuals sampled) exhibited slightly higher associations with host traits when compared to "variable" taxa (not present on all individuals). We identified several key genetic loci and phenotypic traits in Phyllospora that were strongly related to multiple microbial amplicon sequence variants, including taxa with known associations to seaweed defence, disease and tissue degradation. This information on how host-associated microbial communities vary with host traits and the environment enhances our current understanding of how "holobionts" (hosts plus their microbiota) are structured. Such understanding can be used to inform management strategies of these important and vulnerable habitats.

Adjuvant and post-surgical treatment in high-grade epithelial ovarian cancer.

Cytoreductive surgery is the mainstay of treatment for high-grade epithelial ovarian cancer. Although for early stage disease outcomes following surgery alone are good, the risk of recurrence necessitates adjuvant chemotherapy for the majority of patients. Post-operative chemotherapy in advanced-stage disease, or neoadjuvant chemotherapy followed by surgery has improved progression-free survival (PFS) and overall survival (OS). However, despite the use of chemotherapy, the rate of recurrence remains high. In recent years, there has been considerable increase in knowledge regarding the biology of ovarian cancer, which has led to a journey of drug discovery, facilitating the use of novel targeted agents such as VEGF inhibitors and, more recently, PARP inhibitors in the first-line treatment of ovarian cancer. Here, we outline the current evidence-based guidance for systemic therapies in ovarian cancer and highlight the ongoing research to improve patient outcomes.

Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost.

Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England (n = 142) were examined. Their costs in comparison to regular protein-containing (n = 182) and 'free-from' products (n = 135) were also analysed. Similar foods were grouped into subgroups (n = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups (n = 39/40) were more expensive than regular and 'free-from' food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control.

Molecular analysis of a fungal disease in the habitat-forming brown macroalga Phyllospora comosa (Fucales) along a latitudinal gradient.

Infectious diseases affecting habitat-forming species can have significant impacts on population dynamics and alter the structure and functioning of marine ecosystems. Recently, a fungal infection was described as the causative agent of necrotic lesions on the stipe of the forest-forming macroalga Phyllospora comosa, a disease named "stipe rot" (SR). Here, we developed a quantitative PCR (qPCR) method for rapid detection and quantification of this pathogen, which was applied to evaluate the level of SR infection in eight P. comosa populations spanning the entire latitudinal distribution of this species along southeastern Australia. We also investigated the relationship between the abundance and prevalence of Stipe Rot Fungus (SRF) and potential host chemical defenses as well as its relationship with morphological and ecophysiological traits of P. comosa. qPCR estimates of SRF abundance reflected the levels of infection estimated by visual assessment, with higher numbers of SRF copies being observed in individuals showing high or intermediate levels of visual symptoms of SR. Concordance of conventional PCR and visual assessments was 92 and 94%, respectively, compared to qPCR detection. SRF prevalence was positively related to fucoxanthin content and herbivory, but not significant related to other traits measured (phlorotannin content, total length, thallus diameter, stipe width, number of branches, frond width, fouling, bleaching, gender, and photosynthetic efficiency). These results provide confidence for previous reports of this disease based upon visual assessments only, contribute to the development of monitoring and conservation strategies for safeguarding P. comosa forests, and generate insights into potential factors influencing host-pathogen interactions in this system.

Conservation genomics of a critically endangered brown seaweed.

Seaweeds provide valuable ecosystem services, but many are undergoing global decline due to climate and anthropogenic stressors. The brown macroalga, Nereia lophocladia (hereafter called Nereia), is among only a handful of seaweeds globally to be listed as critically endangered and is only described from two known locations, but there exists little knowledge about this species. Here, we combine field surveys to verify the distribution of Nereia, with cutting-edge genomics to determine genetic diversity and population structure, and inform ongoing conservation actions. We expand Nereia's known distribution from one to seven locations along a 70-km long coastal stretch in New South Wales but reveal small population sizes at some sites (as few as 8 individuals despite extensive searching). A total of 1,261 genome-wide SNPs were retained from 70 individuals after filtering, and 304 outlier loci under putative selection were detected by one of three methods. Populations showed low genetic diversity (mean expected heterozygosity HE  = 0.055 ± 0.014) and high levels of inbreeding within populations (mean FIS  = 0.721 ± 0.085), along with high genetic differentiation among sites (mean FST  = 0.276), which may increase susceptibility to future environmental change and decrease the species' ability to recover after loss. Given these findings, we recommend the consideration of both in situ and ex situ conservation measures for Nereia, as well as further research into the species' ecology and biology. Nereia remains of conservation concern and its listing as critically endangered is justified until further investigation elucidates the full distribution and adaptive capacity of the species.

The role of MET in chemotherapy resistance.

Chemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET's role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.

Genomic vulnerability of a dominant seaweed points to future-proofing pathways for Australia's underwater forests.

Globally, critical habitats are in decline, threatening ecological, economic and social values and prompting calls for 'future proofing' efforts that enhance resilience to climate change. Such efforts rely on predicting how neutral and adaptive genomic patterns across a species' distribution will change under future climate scenarios, but data is scant for most species of conservation concern. Here, we use seascape genomics to characterise genetic diversity, structure and gene-environmental associations in a dominant forest-forming seaweed, Phyllospora comosa, along its entire latitudinal (12° latitude), and thermal (~14°C) range. Phyllospora showed high connectivity throughout its central range, with evidence of genetic structure and potential selection associated with sea surface temperatures (SSTs) at its rear and leading edges. Rear and leading-edge populations harboured only half the genetic diversity of central populations. By modelling genetic turnover as a function of SST, we assessed the genomic vulnerability across Phyllospora's distributional range under climate change scenarios. Despite low diversity, range-edge populations were predicted to harbour beneficial adaptations to marginal conditions and overall adaptability of the species may be compromised by their loss. Assisted gene flow from range edge populations may be required to enhance adaptation and increase resilience of central and leading-edge populations under warming oceans. Understanding genomic vulnerability can inform proactive restoration and future-proofing strategies for underwater forests and ensure their persistence in changing oceans.

Milestones for autonomous in vivo microrobots in medical applications.

In light of recent developments within both health care and robotics, the use of robots within the human body has become attainable. Here we discuss the milestones for the realization of autonomous microrobots in medical applications. The desired tasks were classified by identifying the difficulties and requirements faced by the robot. In addition, we classified the levels of autonomy seen in microrobots for these uses. The aim of this article is to provide readers with a good understanding of the current state and future possibilities in this field.

Special Low Protein Foods in the UK: An Examination of Their Macronutrient Composition in Comparison to Regular Foods.

Special low protein foods (SLPFs) are essential in a low phenylalanine diet for treating phenylketonuria (PKU). With little known about their nutritional composition, all SLPFs on UK prescription were studied (n = 146) and compared to equivalent protein-containing foods (n = 190). SLPF nutritional analysis was obtained from suppliers/manufacturers. Comparable information about regular protein-containing foods was obtained from online UK supermarkets. Similar foods were grouped together, with mean nutritional values calculated for each subgroup (n = 40) and percentage differences determined between SLPFs and regular food subgroups. All SLPF subgroups contained 43-100% less protein than regular foods. Sixty-three percent (n = 25/40) of SLPF subgroups contained less total fat with palm oil (25%, n = 36/146) and hydrogenated vegetable oil (23%, n = 33/146) key fat sources. Sixty-eight percent (n = 27/40) of SLPF subgroups contained more carbohydrate, with 72% (n = 105/146) containing added sugar. Key SLPF starch sources were maize/corn (72%; n = 105/146). Seventy-seven percent (n = 113/146) of SLPFs versus 18% (n = 34/190) of regular foods contained added fibre, predominantly hydrocolloids. Nine percent of SLPFs contained phenylalanine > 25 mg/100 g and sources of phenylalanine/protein in their ingredient lists. Stricter nutritional composition regulations for SLPFs are required, identifying maximum upper limits for macronutrients and phenylalanine, and fat and carbohydrate sources that are associated with healthy outcomes.

Derived neutrophil to lymphocyte ratio as a prognostic factor in patients with advanced colorectal cancer according to RAS and BRAF status: a post-hoc analysis of the MRC COIN study.

The phase III Continuous or Intermittent (COIN) trial failed to show a benefit in overall survival (OS) of cetuximab in combination with chemotherapy for patients with metastatic colorectal cancer. High derived neutrophil to lymphocyte ratio (dNLR) has been shown to be prognostic in patients with metastatic colorectal cancer. The aim of this analysis is to evaluate dNLR as a predictive biomarker of the survival according to RAS and BRAF mutations status within the COIN trial. A post-hoc exploratory analysis of the COIN trial arms A and B was carried out. All patients with available white blood cell and neutrophil data were analysed. The dNLR was calculated using a formula that has previously shown predictive power in cancer patients: dNLR=ANC/(WBC-ANC). A high dNLR was defined as a value of 2.2 or more. dNLR was correlated with clinical outcomes using Kaplan-Meier and Cox regression analysis. A total of 1603 patients were assigned to the oxaliplatin-based chemotherapy (arm A, N=815) or oxaliplatin-based chemotherapy plus cetuximab (arm B, N=815) arms. There was a strong association between dNLR level and overall survival (OS) using Kaplan-Meier analysis. In all mutation groups, dNLR less than 2.2 was associated with better OS compared to dNLR of 2.2 or more. The median OS in patients with wild-type disease (dNLR<2.2 vs. dNLR≥2.2) was 22.8 versus 13.1 months [hazard ratio (HR)=1.33]; 16.9 versus 11.8 months (HR=1.36) in patients with RAS mutant tumours; and 12.6 versus 6.8 months (HR=1.67) in patients with BRAF mutant tumours. In patients with dNLR less than 2.2, the median OS was 19.2 months in arm A compared to 18.0 months in arm B (HR=1.11). Among patients with dNLR greater than or equal to 2.2, the median OS was 13.0 months in arm A compared with 13.1 months in arm B (HR=0.96). dNLR is strongly prognostic for survival in all mutation groups. dNLR does not predict for benefit from the addition of cetuximab.

High-resolution photo-mosaic time-series imagery for monitoring human use of an artificial reef.

Successful marine management relies on understanding patterns of human use. However, obtaining data can be difficult and expensive given the widespread and variable nature of activities conducted. Remote camera systems are increasingly used to overcome cost limitations of conventional labour-intensive methods. Still, most systems face trade-offs between the spatial extent and resolution over which data are obtained, limiting their application. We trialed a novel methodology, CSIRO Ruggedized Autonomous Gigapixel System (CRAGS), for time series of high-resolution photo-mosaic (HRPM) imagery to estimate fine-scale metrics of human activity at an artificial reef located 1.3 km from shore. We compared estimates obtained using the novel system to those produced with a web camera that concurrently monitored the site. We evaluated the effect of day type (weekday/weekend) and time of day on each of the systems and compared to estimates obtained from binocular observations. In general, both systems delivered similar estimates for the number of boats observed and to those obtained by binocular counts; these results were also unaffected by the type of day (weekend vs. weekday). CRAGS was able to determine additional information about the user type and party size that was not possible with the lower resolution webcam system. However, there was an effect of time of day as CRAGS suffered from poor image quality in early morning conditions as a result of fixed camera settings. Our field study provides proof of concept of use of this new cost-effective monitoring tool for the remote collection of high-resolution large-extent data on patterns of human use at high temporal frequency.

Coma query cause.

A 54-year-old woman with coeliac disease was admitted to hospital electively for supplemental nutrition. Shortly after feeding started she deteriorated into a hyperammonemic coma with refeeding syndrome, requiring an extensive intensive care admission. Urea cycle disorders were investigated and a biochemical diagnosis of ornithine transcarbamylase deficiency was made. This is a rare diagnosis in the adult population. This case report summarises protein metabolism, urea cycle disorders and the challenges of management.

A cross-sectional study of the individual, social, and built environmental correlates of pedometer-based physical activity among elementary school children.

BACKGROUND: Children who participate in regular physical activity obtain health benefits. Preliminary pedometer-based cut-points representing sufficient levels of physical activity among youth have been established; however limited evidence regarding correlates of achieving these cut-points exists. The purpose of this study was to identify correlates of pedometer-based cut-points among elementary school-aged children. METHOD: A cross-section of children in grades 5-7 (10-12 years of age) were randomly selected from the most (n = 13) and least (n = 12) 'walkable' public elementary schools (Perth, Western Australia), stratified by socioeconomic status. Children (n = 1480; response rate = 56.6%) and parents (n = 1332; response rate = 88.8%) completed a survey, and steps were collected from children using pedometers. Pedometer data were categorized to reflect the sex-specific pedometer-based cut-points of ≥15000 steps/day for boys and ≥12000 steps/day for girls. Associations between socio-demographic characteristics, sedentary and active leisure-time behavior, independent mobility, active transportation and built environmental variables - collected from the child and parent surveys - and meeting pedometer-based cut-points were estimated (odds ratios: OR) using generalized estimating equations. RESULTS: Overall 927 children participated in all components of the study and provided complete data. On average, children took 11407 ± 3136 steps/day (boys: 12270 ± 3350 vs. girls: 10681 ± 2745 steps/day; p < 0.001) and 25.9% (boys: 19.1 vs. girls: 31.6%; p < 0.001) achieved the pedometer-based cut-points.After adjusting for all other variables and school clustering, meeting the pedometer-based cut-points was negatively associated (p < 0.05) with being male (OR = 0.42), parent self-reported number of different destinations in the neighborhood (OR 0.93), and a friend's (OR 0.62) or relative's (OR 0.44, boys only) house being at least a 10-minute walk from home. Achieving the pedometer-based cut-points was positively associated with participating in screen-time < 2 hours/day (OR 1.88), not being driven to school (OR 1.48), attending a school located in a high SES neighborhood (OR 1.33), the average number of steps among children within the respondent's grade (for each 500 step/day increase: OR 1.29), and living further than a 10-minute walk from a relative's house (OR 1.69, girls only). CONCLUSIONS: Comprehensive multi-level interventions that reduce screen-time, encourage active travel to/from school and foster a physically active classroom culture might encourage more physical activity among children.