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.
Adjuvant and post-surgical treatment in high-grade epithelial ovarian cancer Wood, Georgina E.; Ledermann, Jonathan A.
Baillière's best practice & research. Clinical obstetrics & gynaecology/Baillière's best practice and research in clinical obstetrics and gynaecology,
January 2022, 2022-Jan, 2022-01-00, 20220101, Letnik:
78
Journal Article
Recenzirano
Odprti dostop
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.
•Chemotherapy after surgery is a key component of treatment for advanced disease and early-stage disease at high risk of relapse.•Improved understanding of the biology of ovarian cancer has led to integration of targeted therapies into treatment regimens.•Genomic testing is recommended for all patients with high-grade ovarian cancers and is now integral to management.•Prevention of first relapse is the key objective to improve survival.
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.
Understanding genomic vulnerability can inform proactive restoration and future‐proofing strategies for underwater forests and ensure their persistence in changing oceans. Here, we developed a genomic toolbox to inform future‐proofing strategies for Phyllospora comosa, an endemic, forest‐forming seaweed inhabiting the south‐eastern Australian coastline that supports vital ecosystem functions, unique biodiversity and economic values.
Marine heatwaves (MHWs), increasing in duration and intensity because of climate change, are now a major threat to marine life and can have lasting effects on the structure and function of ...ecosystems. However, the responses of marine taxa and ecosystems to MHWs can be highly variable, making predicting and interpreting biological outcomes a challenge. Here, we review how biological responses to MHWs, from individuals to ecosystems, are mediated by fine‐scale spatial variability in the coastal marine environment (hereafter, local gradients). Viewing observed responses through a lens of ecological theory, we present a simple framework of three ‘resilience processes’ (RPs) by which local gradients can influence the responses of marine taxa to MHWs. Local gradients (1) influence the amount of stress directly experienced by individuals, (2) facilitate local adaptation and acclimatization of individuals and populations, and (3) shape community composition which then influences responses to MHWs. We then synthesize known examples of fine‐scale gradients that have affected responses of benthic foundation species to MHWs, including kelp forests, coral reefs, and seagrass meadows and link these varying responses to the RPs. We present a series of case studies from various marine ecosystems to illustrate the differential impacts of MHWs mediated by gradients in both temperature and other co‐occurring drivers. In many cases, these gradients had large effect sizes with several examples of local gradients causing a 10‐fold difference in impacts or more (e.g., survival, coverage). This review highlights the need for high‐resolution environmental data to accurately predict and manage the consequences of MHWs in the context of ongoing climate change. While current tools may capture some of these gradients already, we advocate for enhanced monitoring and finer scale integration of local environmental heterogeneity into climate models. This will be essential for developing effective conservation strategies and mitigating future marine biodiversity loss.
This review paper explores how local environmental variation influences the responses of marine life to increasingly severe marine heatwaves (MHWs). It presents a framework of three ‘resilience processes’ (RPs) through which fine‐scale spatial variability mediates the impacts of heatwaves on marine ecosystems, from individual organisms to entire communities. The paper emphasizes the importance of high‐resolution environmental data and improved climate models for predicting and managing the consequences of MHWs in a changing climate.
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.
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.
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.
Global habitat deterioration of marine ecosystems has led to a need for active interventions to halt or reverse the loss of ecological function. Restoration has historically been a key tool to ...reverse habitat loss and restore functions, but the extent to which this will be sufficient under future climates is uncertain. Emerging genetic technologies now provide the ability for restoration to proactively match adaptability of target species to predicted future environmental conditions, which opens up the possibility of boosting resistance to future stress in degraded and threatened habitats. As such, the choice of whether to restore to historical baselines or anticipate the future remains a key decision that will influence restoration success in the face of environmental and climate change. Here, we present an overview of the different motives for restoration – to recover or revive lost or degraded habitats to extant or historical states, or to reinforce or redefine for future conditions. We focus on the genetic and adaptive choices that underpin each option and subsequent consequences for restoration success. These options span a range of possible trajectories, technological advances and societal acceptability, and represent a framework for progressing restoration of marine habitat forming species into the future.
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.
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 (
= 146) and compared to equivalent protein-containing foods (
= 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 (
= 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 (
= 25/40) of SLPF subgroups contained less total fat with palm oil (25%,
= 36/146) and hydrogenated vegetable oil (23%,
= 33/146) key fat sources. Sixty-eight percent (
= 27/40) of SLPF subgroups contained more carbohydrate, with 72% (
= 105/146) containing added sugar. Key SLPF starch sources were maize/corn (72%;
= 105/146). Seventy-seven percent (
= 113/146) of SLPFs versus 18% (
= 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.
Kelp forests are highly productive foundation species along much of the world’s coastline. As a result, kelp are crucial to the ecological, social, and economic well-being of coastal communities. ...Yet, due to a combination of acute and chronic stressors, kelp forests are under threat and have declined in many locations worldwide. Active restoration of kelp ecosystems is an emerging field that aims to reverse these declines by mitigating negative stressors and then, if needed, introducing biotic material into the environment. To date, few restoration efforts have incorporated positive species interactions. This gap presents a potential shortcoming for the field as evidence from other marine ecosystems illustrates that the inclusion of positive species interactions can enhance restoration success. Additionally, as the climate continues to warm, this approach will be particularly pertinent as positive interactions can also expand the range of physical conditions under which species can persist. Here we highlight how practitioners can use positive density dependence within and amongst kelp species to increase the chances of restoration success. At higher trophic levels, we emphasize how co-restoring predators can prime ecosystems for restoration. We also investigate how emerging technologies in genetic and microbial selection and manipulation can increase the tolerance of target species to warming and other stressors. Finally, we provide examples of how we can use existing anthropogenic activities to facilitate restoration while performing alternative purposes. As kelp forests continue to decline and the field of kelp restoration continues to develop, it is also important that we monitor these potential advancements and ensure they do not have unintended ecosystem effects, particularly with untested techniques such as genetic and microbial manipulations. Nevertheless, incorporating positive species interactions into future restoration practice stands to promote a more holistic form of restoration that also increases the likelihood of success in a shifting seascape.
...climate change, anthropogenic pressures and other biotic/abiotic factors in the past decade have imposed unparalleled impacts on the diversity, distribution, reproduction, population structure, ...biogeography and ecological function of seaweeds globally (Breeman, 1990; Müller et al., 2009; Martínez et al., 2018; Fernández et al., 2019; Song et al., 2021; Bringloe et al., 2022). There are a number of research gaps that still need to be investigated in order to better understand the drivers of diversity and the response of seaweeds under climate change: (a) How do different seaweed species respond to the interactive effects of biotic and abiotic factors? (b) How does genetic variation translate into fitness variation in natural population? (c) How does eco-physiological performance enhance resilience and adaptability to a changing environment? The response process involved protein synthesis and processing, fatty acid and energy metabolism, and protein folding and stability. The contribution “Xanthophyll cycle-related non-photochemical quenching protects Sargassum thunbergii from high light-induced photoinhibition” by Nan et al. examined the photosynthetic performance and xanthophyll cycle activity of S. thunbergii in response to high light using chlorophyll fluorescence and high-performance liquid chromatography (HPLC).
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