Essays in biochemistry最新文献

Glycolytic oscillations have been studied for well over 60 years, but aspects of their function, and mechanisms of regulation and synchronisation remain unclear. Glycolysis is amenable to mechanistic mathematical modelling, as its components have been well characterised, and the system can be studied at many organisational levels: in vitro reconstituted enzymes, cell free extracts, individual cells, and cell populations. In recent years, the emergence of individual cell analysis has opened new ways of studying this intriguing system.

Background: Placement of peripheral intra-venous cannulas and epicutaneo-caval catheters is routinely performed in in Neonatal Intensive Care Unit (NICU), and both devices require visible superficial veins easy to cannulate. NICU patients are intrinsically characterized by poor and fragile vein asset, so that puncture and cannulation of superficial veins is often a challenge even for trained clinicians and cannulation frequently results in a stressful, painful, difficult procedure.

Methods and results: Rapid Superficial Vein Assessment is meant to offer a systematic pre-procedural evaluation of all superficial veins of the newborn, so to allow a rational choice of the best insertion site, tailored on the single patient, and optimized for the specific type of venous access device. The superficial veins are examined systematically, both with and without NIR technology, exploring seven skin areas in the following order: (1) medial malleolus, (2) lateral malleolus, (3) retro-popliteal fossa, (4) back of the hand and wrist, (5) antecubital fossa, (6) anterior scalp surface, and (7) posterior scalp surface.

Conclusions: The aim of the protocol is to increase the first attempt success rate and reduce the duration of the procedure, the number of attempts for single patient and possibly to limit complications, stress, and pain in neonates.

If the biological world is one thing it is variable. As scientists we seek to measure, quantify and explain the causes of this variation. The approach we take to this is remarkably similar whether our research is exploring global temperature, blood pressure, cancer incidence or enzyme kinetics. This approach involves defining clear research questions and applying statistical methods to answer them robustly. This article will introduce a practical example that will be used throughout, specifically whether genetic variation can explain variation in coffee consumption. We assume little experience with statistics and walk through the statistical approach that biologists can use, firstly by describing our data with summary statistics and then by using statistical tests to help arrive at answers to our research question. A General Linear Model (GLM) approach will be used as this is what many common statistical tests are. We explore how to visualise and report results, while checking the assumptions of our analysis. The better we can understand and apply statistics to biological problems, the better we can communicate results and future research to others. The popular statistical programming language R will be used throughout.

The introduction of immunotherapy, in particular immune checkpoint inhibition, has revolutionised the treatment of a range of tumours; however, only a minority of patients respond to these therapies. Understanding the mechanisms by which different immune checkpoint inhibitors work will be critical for both predicting patients who will respond and to developing rational combination therapies to extend these benefits further. The initiation and maintenance of anti-tumour T cell responses is a complicated process split between both the tumour microenvironment and the tumour draining lymph node. As understanding of this process has increased, it has become apparent that immune checkpoint inhibitors can act both within the tumour and in the draining lymph node and that they can target both already activated T cells as well as stimulating the priming of novel T cell clones. Currently, it seems likely that immune checkpoint inhibition acts both within the tumour and in the tumour draining lymph node both reinvigorating existing clones and driving further de novo priming of novel clones. The relative contributions of these sites and targets may depend on the type of model being used and the timeline of the response. Shorter models emphasise the effect of reinvigoration in the absence of recruitment of new clones but studies spanning longer time periods examining T cell clones in patients demonstrate clonal replacement. Ultimately, further work is needed to determine which of the diverse effects of immune checkpoint inhibitors are the fundamental drivers of anti-tumour responses in patients.

Today, it is accepted that the ability to evade the attention of the immune system is an essential hallmark of cancer. Critically, as tumours progress, cancer cells can protect themselves from the immune system's natural ability to fight the disease. This observation has led to an explosion of basic research to discover how to restore anti-tumour immunity for advancing cancer treatment. Clinical successes have been achieved following the approval of checkpoint inhibitor therapy to effectively prolong the life of many cancer patients with malignant disease. However, despite impressive survival gains, there is still a high variability of responses between different types of cancer and many patients still fail to respond. The disappointing findings that have been documented over the many clinical trials performed so far coincide with a much more complex view of immuno-oncology that has emerged from technological advances in functional fluorescent imaging techniques, high-throughput RNA sequencing and single-cell mass cytometry. The themed topic 'Immuno-Oncology' captures the contemporary understanding that individual tumours comprise remarkable mixtures of immune cell populations that actively contribute to neoplastic growth, invasion and metastasis through reciprocal and dynamic interactions with cancer cells. In the context of this new knowledge, the reviews discuss novel ideas of therapeutic opportunities for cancer. We would like to thank the authors for their excellent contributions.

Neutrophils, until recently, have typically been considered a homogeneous population of terminally differentiated cells with highly conserved functions in homeostasis and disease. In hepatocellular carcinoma (HCC), tumour-associated neutrophils (TANs) are predominantly thought to play a pro-tumour role, promoting all aspects of HCC development and progression. Recent developments in single-cell technologies are now providing a greater insight and appreciation for the level of cellular heterogeneity displayed by TANs in the HCC tumour microenvironment, which we have been able to correlate with other TAN signatures in datasets for gastric cancer, pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). TANs with classical pro-tumour signatures have been identified as well as neutrophils primed for anti-tumour functions that, if activated and expanded, could become a potential therapeutic approach. In recent years, therapeutic targeting of neutrophils in HCC has been typically focused on impairing the recruitment of pro-tumour neutrophils. This has now been coupled with immune checkpoint blockade with the aim to stimulate lymphocyte-mediated anti-tumour immunity whilst impairing neutrophil-mediated immunosuppression. As a result, neutrophil-directed therapies are now entering clinical trials for HCC. Pharmacological targeting along with ex vivo reprogramming of neutrophils in HCC patients is, however, in its infancy and a greater understanding of neutrophil heterogeneity, with a view to exploit it, may pave the way for improved immunotherapy outcomes. This review will cover the recent developments in our understanding of neutrophil heterogeneity in HCC and how neutrophils can be harnessed to improve HCC immunotherapy.

Treatment with immune checkpoint inhibitors, widely known as immune checkpoint blockade therapy (ICBT), is now the fourth pillar in cancer treatment, offering the chance of durable remission for patients with advanced disease. However, ICBT fails to induce objective responses in most cancer patients with still others progressing after an initial response. It is necessary, therefore, to elucidate the primary and acquired resistance mechanisms to ICBT to improve its efficacy. Here, we highlight the paradoxical role of the cytokine interferon-γ (IFN-γ) in ICBT response: on the one hand induction of IFN-γ signalling in the tumour microenvironment correlates with good ICBT response as it drives the cellular immune responses required for tumour destruction; nonetheless, IFN-γ signalling is implicated in ICBT acquired resistance. We address the negative feedback and immunoregulatory effects of IFN-γ signalling that promote immune evasion and resistance to ICBT and discuss how these can be targeted pharmacologically to restore sensitivity or circumvent resistance.

Immune checkpoint immunotherapies act to block inhibitory receptors on the surface of T cells and other cells of the immune system. This can increase activation of immune cells and promote tumour clearance. Whilst this is very effective in some types of cancer, significant proportions of patients do not respond to single-agent immunotherapy. To improve patient outcomes, we must first mechanistically understand what drives therapy resistance. Many studies have utilised genetic, transcriptional, and histological signatures to find correlates of effective responses to treatment. It is key that we understand pretreatment predictors of response, but also to understand how the immune system becomes treatment resistant during therapy. Here, we review our understanding of the T-cell signatures that are critical for response, how these immune signatures change during treatment, and how this information can be used to rationally design therapeutic strategies. We highlight how chronic antigen recognition drives heterogeneous T-cell exhaustion and the role of T-cell receptor (TCR) signal strength in exhausted T-cell differentiation and molecular response to therapy. We explore how dynamic changes in negative feedback pathways can promote resistance to single-agent therapy. We speculate that this resistance may be circumvented in the future through identifying the most effective combinations of immunotherapies to promote sustained and durable antitumour responses.

The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.

Focal radiation therapy (RT) has been successfully employed to clinically manage multiple types of cancer for more than a century. Besides being preferentially cytotoxic for malignant cells over their nontransformed counterparts, RT elicits numerous microenvironmental alterations that appear to factor into its therapeutic efficacy. Here, we briefly discuss immunostimulatory and immunosuppressive microenvironmental changes elicited by RT and their impact on tumor recognition by the host immune system.