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Core regulatory circuitries in defining cancer cell identity across the malignant spectrum.
No full textGene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors create and engage super-enhancers by recruiting acetylation writers depositing permissive H3K27ac chromatin marks. These super-enhancers are largely associated with BET proteins, including BRD4, that influence higher-order chromatin structure. The orchestration of these events triggers accessibility of RNA polymerase machinery and the imposition of lineage-specific gene expression. In cancers, CRCs drive cell identity by superimposing developmental programmes on a background of genetic alterations. Further, the establishment and maintenance of oncogenic states are reliant on CRCs that drive factors involved in tumour development. Hence, the molecular dissection of CRC components driving cell identity and cancer state can contribute to elucidating mechanisms of diversion from pre-determined developmental programmes and highlight cancer dependencies. These insights can provide valuable opportunities for identifying and re-purposing drug targets. In this article, we review the current understanding of CRCs across solid and liquid malignancies and avenues of investigation for drug development efforts. We also review techniques used to understand CRCs and elaborate the indication of discussed CRC transcription factors in the wider context of cancer CRC models
The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis
No full textCase Report: Subarachnoid Hemorrhage and Eosinophilic Meningitis due to Disseminated Fascioliasis.
No full textHuman infection with the trematode occurs with a worldwide prevalence of up to 17 million. Sheep and cattle are the normal host. Infection typically results in hepatobiliary disease, but extrahepatic manifestations are occasionally reported. Here, we present the case of a previously healthy 31-year-old Kurdish woman, admitted to hospital with a subarachnoid hemorrhage, eosinophilic meningitis, and lung and liver disease. A diagnosis of infection was made based on strongly positive serology in blood and cerebrospinal fluid. The patient improved following treatment with triclabendazole and prednisolone
Development of the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT).
No full textINTRODUCTION
Do-not-attempt-cardiopulmonary-resuscitation (DNACPR) practice has been shown to be variable and sub-optimal. This paper describes the development of the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT). ReSPECT is a process which encourages shared understanding of a patient's condition and what outcomes they value and fear, before recording clinical recommendations about cardiopulmonary-resuscitation (CPR) within a broader plan for emergency care and treatment.
METHODS
ReSPECT was developed iteratively, with integral stakeholder engagement, informed by the Knowledge-to-Action cycle. Mixed methods included: synthesis of existing literature; a national online consultation exercise; cognitive interviews with users; a patient-public involvement (PPI) workshop and a usability pilot, to ensure acceptability by both patients and professionals.
RESULTS
The majority (89%) of consultation respondents supported the concept of emergency care and treatment plans. Key features identified in the evaluation and incorporated into ReSPECT were: The importance of discussions between patient and clinician to inform realistic treatment preferences and clarity in the resulting recommendations recorded by the clinician on the form. The process is compliant with UK mental capacity laws. Documentation should be recognised across all health and care settings. There should be opportunity for timely review based on individual need.
CONCLUSION
ReSPECT is designed to facilitate discussions about a person's preferences to inform emergency care and treatment plans (including CPR) for use across all health and care settings. It has been developed iteratively with a range of stakeholders. Further research will be needed to assess the influence of ReSPECT on patient-centred decisions, experience and health outcomes
Minimum depths to essential structures in a UK military population using computed tomography: application to stab-resistant body armour.
No full textINTRODUCTION
Edged weapons are a known domestic threat to the police forces of the UK. This threat is mitigated by wearing stab-resistant body armour that is either worn overtly or covertly depending on role. Although the UK military have traditionally focused their body armour design upon ballistic and fragmentation threats, future roles may require protection against an edged weapon threat. Since 2017, UK police body armour requirements for anatomical coverage for both edged weapon and ballistic threats are now based upon the requirements of UK military. This revised coverage may need additional research to determine minimum distances to essential structures.
METHOD
Three entry locations and penetration vectors were chosen using the limited available information in the literature, in combination with a specialist in edged weapons defence. One hundred twenty CT trauma scans of male military service personnel were subsequently analysed to ascertain minimum distances from skin surface to the first structure encountered that is included in essential coverage (heart, aorta, vena cava, liver and spleen) at 3 specific entry points.
RESULTS
Individuals ranged between 18 and 46 years, with a mean body mass index of 24.8. The absolute minimum depth from skin surface to a structure within the auspice of essential coverage was 17 mm to the liver in entry point 3 and 19 mm to the heart in entry point 2.
CONCLUSIONS
Minimum distances to critical structures were significantly larger than those described in previous studies on civilians. This study will be used to supplement existing evidence to support existing UK police requirements for stab-resistant body armour. Using the weapon entry sites and vectors described in this study, overmatching to a behind armour depth of 17 mm would cover all of this population in this study
Small molecule oral targeted therapies in ulcerative colitis.
No full textThe incidence and prevalence of ulcerative colitis are increasing globally. Although the exact cause and pathogenesis of this disease is unclear, research has led to a better understanding of the condition and to identification of new targets for therapy, which in turn has encouraged the development of new therapies. As well as biologic therapies, which have changed the way inflammatory bowel disease is managed, small molecules have been developed for the treatment of ulcerative colitis. These small molecule treatments are orally administered and are likely to bring a substantial shift in the way this chronic disease is treated. Oral therapies offer many advantages over infusion therapies, such as ease of use, increased acceptability by patients, and reduction of cost. This Review focuses not only on oral therapies that have been approved for use in ulcerative colitis, but also on those that are in development, providing a comprehensive overview for clinicians of available oral therapies and drugs that are likely to become available. We have also reviewed drugs that have shown promise in preclinical studies and could be effective future therapies
Clinical considerations in individuals with Alpha-1 Antitrypsin PI*SZ genotype.
No full textAlpha-1 Antitrypsin Deficiency (AATD), characterised by reduced levels or functionality of Alpha-1 Antitrypsin (AAT), is a significantly under-diagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD is based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AAT deficiency, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. The present narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index non-index identification and smoking history. The relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is also explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals
The Liver as an Immunological Barrier Redefined by Single Cell Analysis.
No full textThe liver is a front-line immune tissue that plays a major role in the detection, capture and clearance of pathogens and foreign antigens entering the blood-stream, especially from the gut. Our largest internal organ maintains this immune barrier in the face of constant exposure to external but harmless antigens through a highly specialised network of liver-adapted immune cells. Mapping the immune resident compartment in the liver has been challenging because it requires multimodal single-cell deep phenotyping approaches of often rare cell populations in difficult to access samples. We can now measure the RNA transcripts present in a single cell (scRNA-seq), which is revolutionising the way we characterise cell types. scRNA-seq has been applied to the diverse array of immune cells present in murine and human livers in health and disease. Here we summarise how emerging single cell technologies have advanced or redefined our understanding of the immunological barrier provided by the liver
Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the trial protocol.
No full textINTRODUCTION
Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775).
METHODS AND ANALYSIS
This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B.
ETHICS AND DISSEMINATION
Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences.
TRIAL REGISTRATION NUMBER
ISRCTN76291951 and NCT03028766
