Research Progress on Postoperative Minimal/Molecular Residual Disease Detection in Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%–50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement

The Genome of the Chicken DT40 Bursal Lymphoma Cell Line

The chicken DT40 cell line is a widely used model system in the study of multiple cellular processes due to the efficiency of homologous gene targeting. The cell line was derived from a bursal lymphoma induced by avian leukosis virus infection. In this study we characterized the genome of the cell line using whole genome shotgun sequencing and single nucleotide polymorphism array hybridization. The results indicate that wild type DT40 has a relatively normal karyotype except for whole chromosome copy number gains, and no karyotype variability within stocks. In a comparison to two domestic chicken genomes and the Gallus gallus reference genome we found no unique mutational processes shaping the DT40 genome except for a mild increase in insertion and deletion events, particularly deletions at tandem repeats. We mapped coding sequence mutations that are unique to the DT40 genome; mutations inactivating the PIK3R1 and ATRX genes likely contributed to the oncogenic transformation. In addition to a known avian leukosis virus integration in the MYC gene we detected further integration sites that are likely to de-regulate gene expression. The new findings support the hypothesis that DT40 is a typical transformed cell line with a relatively intact genome, therefore it is well suited to the role of a model system for DNA repair and related processes. The sequence data generated by this study, including a searchable de novo genome assembly and annotated lists of mutated genes, will support future research using this cell line

Knowledge, comprehension, attitude to and practice of the five levels of prevention in child healthcare in a Nigerian teaching hospital

Background: Preventive Paediatrics involves all activities geared towards protecting, promoting and maintaining the health and wellbeing of children. The aim of this study to determine the knowledge, attitude and practice of the five levels of prevention by child-care doctors at the University of Port Harcourt Teaching Hospital. Methods: This was a descriptive cross-sectional survey using a self-administered questionnaire. Information on socio-demographics, knowledge, comprehension and attitude of the respondents towards the five levels of prevention and its utilization by the doctors at the University of Port Harcourt Teaching Hospital was sought. Data were analyzed using descriptive statistics. Results: 295 doctors participated. 26 (8.8%) doctors had good knowledge of the five levels of prevention. As the doctors’ age increased, they were less likely to be knowledgeable about the levels of prevention (OR=0.955; 95% CI: 0.917-0.995; p-value=0.029). Doctors in Pediatrics were four times more likely to be knowledgeable about the levels of prevention than the others (OR=3.637; 95% CI: 1.496-8.844; p-value= 0.004). 287 (97.3%) doctors had good attitude towards preventive activities while practice was by 222 (75.3%). There were no significant differences across gender, age, department, designation and years of practice. Doctors with good knowledge significantly practiced more levels of prevention compared to those with poor knowledge (p=0.049, 0.024, 0.001 and 0.010 respectively).   Conclusions: Majority of the doctors have poor knowledge of the five levels of prevention, despite having a good attitude and practice which suggests a knowledge-practice gap. Interventions to improve doctors’ knowledge are recommended.

A comparative analysis of the mutagenicity of platinum-containing chemotherapeutic agents reveals direct and indirect mutagenic mechanisms.

Platinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance and also induce secondary malignancies. We coupled whole genome sequencing with phenotypic investigations on two cell line models to compare the magnitude and examine the mechanism of mutagenicity of cisplatin, carboplatin and oxaliplatin. Cisplatin induced significantly more base substitution mutations than carboplatin or oxaliplatin when used at equitoxic concentrations on human TK6 or chicken DT40 cells, and also induced the highest number of short insertions and deletions. The analysis of base substitution spectra revealed that all three tested platinum drugs elicit both a direct mutagenic effect at purine dinucleotides, and an indirect effect of accelerating endogenous mutagenic processes, whereas the direct mutagenic effect appeared to correlate with the level of DNA damage caused as assessed through histone H2AX phosphorylation and single-cell agarose gel electrophoresis, the indirect mutagenic effects were equal. The different mutagenicity and DNA-damaging effect of equitoxic platinum drug treatments suggest that DNA damage independent mechanisms significantly contribute to their cytotoxicity. Thus, the comparatively high mutagenicity of cisplatin should be taken into account in the design of chemotherapeutic regimens

APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

The APOBEC mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer

APOBEC3 as a driver of genetic intratumor heterogeneity

Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution

Fast-track pathway for elective caesarean section: a quality improvement initiative to promote day 1 discharge.

Enhanced recovery after surgery (ERAS) aims to improve perioperative care, hasten recovery to the normal physiological state and shorten length of stay (LoS). There is evidence that ERAS programmes following elective caesarean section (ELCS) confer benefit through faster return to physiological state and reduced LoS for mother and baby. Baseline audit of ELCS in 2013 revealed a mean LoS of 3 days. We piloted an ERAS discharge pathway promoting day 2 discharge, which rose from 5.0% to 40.2%. 19.2% of women went home on day 1. Many women fed back that they would prefer day 1 discharge. We hypothesised that a day 1 discharge pathway for low-risk women could benefit both women and services at our maternity unit. From October 2015, we developed a 'fast-track pathway' (FTP) using a Plan-Do-Study-Act approach. Between October 2015 and April 2016, we prospectively audited clinical outcomes, LoS and maternal satisfaction from all women placed on the FTP. We held regular multidisciplinary team meetings to allow contemporaneous analysis. Satisfaction was analysed by Likert scale at postoperative surveys. Women were identified in antenatal clinic after meeting predefined low-risk criteria. 27.3% of women (n=131/479) delivering by ELCS entered the FTP. 76.2% of women on the FTP were discharged on day 1. Mean LoS fell to 1.31 days. 94.2% of women who established breast feeding at day 1 were still breast feeding at 7 days. Overall satisfaction at day 7 was 4.71 on a 5-point Likert scale. 73.1% of women reported good pain control. Additional financial savings are estimated at £99 886 annually. There were no related cases of readmission. Day 1 discharge after ELCS is safe and acceptable in carefully selected, low-risk women and has high satisfaction. There may be resultant financial savings and improved flow through a maternity unit with no detected adverse effect on breast feeding, maternal morbidity or postnatal readmissions

Informed Consent among Hansen’s Disease Patients – A Nigerian Perspective

Background: Informed consent entails providing potential participants with adequate information needed to decide whether or not to participate in research. In Nigeria, Hansen's disease has remained a disease of public health importance. The associated stigmatization often renders patients vulnerable and prone to exploitation. The act of obtaining informed consent from these patients remain an issue of ethical importance. The study aimed to determine the willingness of Hansen's disease patients to give consent to use their data in the form of pictures, videos and/or oral interviews by a third party. Materials and Method: This descriptive cross-sectional study was carried out in three states in Nigeria; Ebonyi, Ogun and Cross River States. Data was collected from consenting participants using researcher-administered semi-structured questionnaires. Results: The study included 93 respondents with a mean (SD) age of 44.9 (20.1) years. The majority 57 (61.29%) of the respondents were farmers while the majority 67 (72.04%) attained primary education. A total of 26 (27.96%) respondents had suffered discrimination in the course of their disease. In their responses, 83 (89.2%) would allow the use of their pictures, 80 (86.0%) their videos and 86 (92.5%) their recorded oral interviews. Among those who would not give consent, the commonest reasons adduced were an intrusion into privacy and lack of trust. Conclusion: Though a majority of the patients would give consent for use of their data intrusion into privacy and lack of trust were major constraints for those not willing to give consent. Caregivers and stakeholders should put more effort into trying to win patients' trust before seeking informed consent

Exploring experiences and impact of the COVID-19 pandemic on young racially minoritised people in the United Kingdom: A Qualitative Study

Within high-income-countries, the COVID-19 pandemic has disproportionately impacted people from racially minoritised backgrounds. There has been significant research interrogating the disparate impact of the virus, and recently, interest in the long-term implications of the global crisis on young people’s mental health and wellbeing. However, less work explores the experiences of young people from racialised backgrounds as they navigate the pandemic, and the specific consequences this has for their mental health. Forty young people (age 16-25) from black, mixed and other minority backgrounds and living in London, participated in consecutive focus group discussions over a two-month period, to explore the impact of the pandemic on their lives and emotional wellbeing. Thematic analysis identified seven categories describing the impact of the pandemic, indicating: deepening of existing socioeconomic and emotional challenges; efforts to navigate racism and difference within the response; and survival strategies drawing on communal and individual resources. Young people also articulated visions for a future public health response which addressed gaps in current strategies. Findings point to the need to contextualise public health responses to the pandemic in line with the lived experiences of racialised young people. We specifically note the importance of long-term culturally and socio-politically relevant support interventions. Implications for policy and practice are discusse