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Genetic perturbation screens have the potential to dissect a wide range of cellular phenotypes. Such screens have historically been difficult in diploid mammalian cells. The recent derivation of haploid embryonic stem cells provides an opportunity to cause

The p63 transcription factor (TP63) is critical in development, growth and differentiation of stratifying epithelia. This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mic

Introduction: Self-administration schemes can have significant impact on a patient's management and treatment of specific diseases. Implementing the self-administration of insulin for inpatients is believed to increase patient's knowledge, understanding, independence and confidence regarding medication to improve outcomes. This study identifies the limited knowledge and access to self-administration schemes for diabetes. Aim: The aim of this scoping review is to collect and review relevant literature surrounding inpatient insulin self-administration schemes and to identify the impact this scheme has on knowledge, confidence, independence, satisfaction, costs and workload for patients, hospitals and staff. This scoping review further aims to highlight the reported limitations regarding self-administration and identify the potential gaps in the evidence-base. Methods: Keywords were searched on MEDLINE (1946 to October Week 4 2022), EMBASE (1974 to 2022 Week 43), Scopus, Web of Science, CINAHL and Google Scholar from October 6th, 2022, to November 8th, 2022. The title, abstract and citations were initially screened using the inclusion and exclusion criteria. Included literature was then screened by a second reviewer. The identified literature described and evaluated inpatient insulin self-administration schemes and summarised according to author and study design. This scoping review did not require ethical approval as it was including information and studies freely available for public domain. Newcastle University Pharmacy Department. Results: Among the 1,159 literature sources identified, 16 literature sources were included in the scoping review. A systematic review and meta-analysis was initially considered but yielded due to the heterogeneity of literature in study design. Nine quantitative and seven qualitative studies assessed individual patient and staff views. They were assessed in ranging time frames up to eight months. Literature evaluated the knowledge, understanding and compliance of patients relating to administration and drug regimens which were measured via questionnaires and interviews. Studies identified short-term costs to outweigh long-term benefits. The majority of patients and staff were significantly satisfied with the implementation of self-administration schemes. Discussion/Conclusion: The implementation of insulin self-administration schemes for inpatients has shown to support patient health and safety, increasing knowledge and compliance. Literature continues to identify the need for extra support and maintenance from healthcare professionals to control diabetes. Self-administration schemes may continue to advance with increased support and engagement. Study limitations were identified to further acknowledged the advancements in time frames, support and sample size and selection for participants, supporting the advancements in self-administration schemes. References: 1. Wright J, Emerson A, Stephens M, Lennan E. Hospital inpatient self-administration of medicine programmes: a critical literature review. Pharmacy World and Science. 2006;28(3):140. 2. Muhammad K, Khan T, Nisar Ur R, Khan Z, Subhan F. Knowledge and attitude regarding insulin self-administration among diabetic patients: a cross-sectional study in a teaching hospital of Khyber-Pakhtunkhwa, Pakistan. Drugs & Therapy Perspectives. 2020;36(6):266-72. 3. Gangopadhyay KK, Ebinesan AD, Mtemererwa B, Marshall C, McGettigan AT, Cope A, et al. The timing of insulin administration to hospital inpatients is unsafe: Patient self-administration may make it safer. Practical Diabetes International. 2008;25(3):96-8. [ABSTRACT FROM AUTHOR]

Background:Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated.Methods:Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified.Results:We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42).Conclusions:These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread. [ABSTRACT FROM AUTHOR]

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approximately 5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11-12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21-q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3-q4 and 18p11.31 and gains of 6p25.1-p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2-11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages. [ABSTRACT FROM AUTHOR]

Despite aggressive salvage regimens, approximately half of all children who suffer a Wilms' tumour recurrence will die of their disease. Although there are increasing data on molecular genetic prognostic factors present in the tumour at diagnosis, there is little information regarding the molecular events that occur with Wilms' tumour progression and relapse. In the present study, microarray-based comparative genomic hybridization (aCGH) analysis has been carried out on 58 Wilms' tumour samples, which included 38 untreated primary and 20 recurrent tumours. A higher degree of copy number changes was observed in the recurrent tumours (33.0% genomic clones) than in the primary tumour (21.2%). Paired analysis highlighted the acquisition of 15q gain with high levels of IGF1R expression in the tumour recurrence in two cases. The most statistically significant abnormality acquired between diagnosis and relapse was loss of 17p. One case that experienced 17p loss was classified as favourable histology at diagnosis, but exhibited diffuse anaplasia at recurrence and had a homozygous TP53 deletion. Another instructive case with a constitutional 11p13 deletion presented with bilateral tumours and suffered two subsequent recurrences in the left kidney. A somatic WT1 mutation was found only in the right kidney tumour, while the constitutional 11p13 deletion was the only abnormality detected in the initial left kidney tumour by aCGH. The two subsequent relapses in the left kidney contained an accumulation of additional genetic alterations, including an independent WT1 mutation. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]