Context dependent activity of p63-bound gene regulatory elements.

The p53 family of transcription factors regulate numerous organismal processes including the development of skin and limbs, ciliogenesis, and preservation of genetic integrity and tumor suppression. p53 family members control these processes and gene expression networks through engagement with DNA sequences within gene regulatory elements. Whereas p53 binding to its cognate recognition sequence is strongly associated with transcriptional activation, p63 can mediate both activation and repression. How the DNA sequence of p63-bound gene regulatory elements is linked to these varied activities is not yet understood. Here, we use massively parallel reporter assays (MPRA) in a range of cellular and genetic contexts to investigate the influence of DNA sequence on p63-mediated transcription. Most regulatory elements with a p63 response element motif (p63RE) activate transcription, with those sites bound by p63 more frequently or adhering closer to canonical p53 family response element sequences driving higher transcriptional output. The most active regulatory elements are those also capable of binding p53. Elements uniquely bound by p63 have varied activity, with p63RE-mediated repression associated with lower overall GC content in flanking sequences. Comparison of activity across cell lines suggests differential activity of elements may be regulated by a combination of p63 abundance or context-specific cofactors. Finally, changes in p63 isoform expression dramatically alters regulatory element activity, primarily shifting inactive elements towards a strong p63-dependent activity. Our analysis of p63-bound gene regulatory elements provides new insight into how sequence, cellular context, and other transcription factors influence p63-dependent transcription. These studies provide a framework for understanding how p63 genomic binding locally regulates transcription. Additionally, these results can be extended to investigate the influence of sequence content, genomic context, chromatin structure on the interplay between p63 isoforms and p53 family paralogs.

E-cigarette side effects in otolaryngology: unveiling the vape mirage.

DATA SOURCES: The following databases were searched for publications up to May 2020: Web of Science, EMBASE, CENTRAL, Medline and CINAHL. Additionally, previously published reviews were hand searched. STUDY SELECTION: Clinical studies conducted in English language were considered, encompassing cohorts of more than four vaping individuals who have encountered inadvertent side effects. Both adult and paediatric populations were included. In vitro, animal studies and systematic or literature reviews were excluded from the analysis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened 1125 studies following deduplication. Two-hundred and eight full-text studies were assessed for eligibility. RESULTS: Thirty-two studies met the inclusion criteria. Diverse study designs were included, comprising of cross-sectional, randomised controlled trials, case-control studies, cohort studies, case series investigations and non-randomised trials. Of note, four studies focused on paediatric patients. Most reported side effects were cough, throat and mouth irritation and intra-oral lesions. CONCLUSIONS: While the direct side effects of e-cigarettes are well-documented, the long-term effects remain uncertain.

Appropriateness of two-week wait head and neck cancer referrals to a district general hospital.

Objectives The NHS advise urgent referral of patients with suspected head and neck cancers to secondary care to be seen via a two-week wait pathway. The objective of this review was to analyse the two-week wait head and neck cancer referrals to a district general hospital and to identify the prevalence of oral cancer.Materials and methods Patients referred via an urgent two-week wait cancer pathway during the period of 12 October 2020 to 19 January 2022 were identified. Data were extracted and analysed for referral source, patient sex, whether or not a biopsy was undertaken, and the number of patients with a final positive cancer diagnosis.Results Overall, 883 two-week wait referrals were received. Most referrals came from general medical practitioners (50%) followed by general dental practitioners (37%). A total of 379 patients (46%) underwent a biopsy, special investigations, or internal referral to another speciality. The overall prevalence of cancer was 6.2%. Most referrals received were for commonly occurring benign conditions.Conclusion Despite many two-week wait suspected cancer referrals, only a small percentage of patients go on to be diagnosed with head and neck cancer. These results highlight the number of avoidable referrals, which ultimately impact patient waiting lists and clinician time.

Shared Gene Targets of the ATF4 and p53 Transcriptional Networks.

The master tumor suppressor p53 regulates multiple cell fate decisions, such as cell cycle arrest and apoptosis, via transcriptional control of a broad gene network. Dysfunction in the p53 network is common in cancer, often through mutations that inactivate p53 or other members of the pathway. Induction of tumor-specific cell death by restoration of p53 activity without off-target effects has gained significant interest in the field. In this study, we explore the gene regulatory mechanisms underlying a putative anticancer strategy involving stimulation of the p53-independent integrated stress response (ISR). Our data demonstrate the p53 and ISR pathways converge to independently regulate common metabolic and proapoptotic genes. We investigated the architecture of multiple gene regulatory elements bound by p53 and the ISR effector ATF4 controlling this shared regulation. We identified additional key transcription factors that control basal and stress-induced regulation of these shared p53 and ATF4 target genes. Thus, our results provide significant new molecular and genetic insight into gene regulatory networks and transcription factors that are the target of numerous antitumor therapies.

Shared gene targets of the ATF4 and p53 transcriptional networks.

The master tumor suppressor p53 regulates multiple cell fate decisions, like cell cycle arrest and apoptosis, via transcriptional control of a broad gene network. Dysfunction in the p53 network is common in cancer, often through mutations that inactivate p53 or other members of the pathway. Induction of tumor-specific cell death by restoration of p53 activity without off-target effects has gained significant interest in the field. In this study, we explore the gene regulatory mechanisms underlying a putative anti-cancer strategy involving stimulation of the p53-independent Integrated Stress Response (ISR). Our data demonstrate the p53 and ISR pathways converge to independently regulate common metabolic and pro-apoptotic genes. We investigated the architecture of multiple gene regulatory elements bound by p53 and the ISR effector ATF4 controlling this shared regulation. We identified additional key transcription factors that control basal and stress-induced regulation of these shared p53 and ATF4 target genes. Thus, our results provide significant new molecular and genetic insight into gene regulatory networks and transcription factors that are the target of numerous antitumor therapies.

How harmful are e-cigarettes to the head and neck cells?

Data sources Medline, Cumulative Index to Nursing and Allied Health Literature, Chemical Abstracts Plus, Dentistry and Oral Sciences and Web of Science databases, as well as grey literature, were searched for publications up to December 2020.Study selection Search terms and concepts were mentioned in line with clear PICOS (population, intervention, comparison, outcomes and study) criteria. Inclusion and exclusion criteria were outlined. All study designs were considered.Data extraction and synthesis Two independent reviewers screened 233 articles using Rayyan software. In total, 49 full-text articles were retrieved.Results Overall, 18 studies fit the inclusion criteria, of which two were clinical trials and sixteen were in vitro research. Varying strengths of nicotine concentration were examined for toxicity on head and neck cells. The use of electronic cigarettes (e-cigarettes) caused changes to cell size and shape and reduced cell viability and cell proliferation.Conclusions Although less harmful than tobacco smoke, e-cigarettes appear to induce damaging changes in head and neck cells.

Five-year prospective fistula audit in a single center. TIG training negates consultant learning curve, but surgeons should beware the mid-range palatal defect.

The aim of primary palatoplasty is to achieve optimum speech with minimal morbidity. Symptomatic fistulae are well-recognised complications of palatoplasty and may require additional surgical intervention, increasing the burden of care. Our aims were to better understand fistula experience in our unit and compare fistula rates between an established consultant and a newly appointed training interface group (TIG) trained consultant. Post-operative fistulae were prospectively and independently recorded by Cleft Clinical Nurse Specialists as part of routine 6-week post-operative reviews. Cleft type and intra-operative hard-soft palate junction (HSPJ) width were prospectively recorded by operating surgeons. Data were collated and analysed using Microsoft Excel. Between 1 January 2014 and 31 December 2018, 250 primary palatoplasties were performed. The overall fistula rate was 8% (0% SMCP, ICP 7%, UCLP 8%, BCLP 22%). Fistulae clustered in clefts with a mid-range HSPJ width of 12-16 mm. Numerically, fistula rates remained similar over time despite increased unit activity (doubling of primary surgeries in 2017 and 2018). There was no significant difference in fistulae rates between surgeons (P > 0.05). Overall fistulae rate compared favourably with published data. TIG fellowships were designed in the context of cleft surgery to address issues relating to steep operative learning curves. These data demonstrate that results from a newly appointed TIG-trained surgeon are comparable to that of an established TIG-trained surgeon. Data also suggest surgeons should be aware of the risk of fistulae in the mid-range palatal defect and in HSPJ widths of 12-16 mm.

Guided tissue regeneration techniques involving blood-derived products in periradicular surgery: a systematic review and meta-analysis protocol.

OBJECTIVE: The objective of this review is to evaluate the clinical outcomes of standard periradicular surgery versus periradicular surgery with the use of guided tissue regeneration techniques involving blood-derived products in patients undergoing periradicular surgery. INTRODUCTION: Guided tissue regeneration techniques have been available in dentistry for decades. Primarily used during periodontal surgery and implant placement, their usefulness in periapical surgery has been garnering increased attention. According to current available evidence, guided tissue regeneration can improve clinical patient outcomes. No systematic reviews have been carried out to investigate guided tissue regeneration techniques involving blood-derived products in periradicular surgery. INCLUSION CRITERIA: Randomized controlled trials that investigate the outcomes of guided tissue regeneration techniques involving blood-derived products versus standard periradicular surgery technique, will be included for review. Studies will be excluded if they contain patients who have previously undergone periradicular surgery or the treatment was carried out on unrestorable teeth (ie, due to periodontal disease or root fractures). METHODS: The databases MEDLINE, Embase, Dentistry and Oral Sciences Source, and Cochrane CENTRAL will be used to locate published reports of studies. Reference lists of relevant past systematic reviews will be used to identify further studies. Unpublished studies will be sought using international trials registries and repositories. Two reviewers will carry out independent screening of records for inclusion and the selected studies will be critically appraised prior to data extraction and synthesis. Meta-analysis will be performed if appropriate. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020222663.