Long non-coding RNAs (lncRNAs) are frequently dysregulated in many human cancers. We sought to identify candidate oncogenic lncRNAs in human colon tumors by utilizing RNA sequencing data from 22 ...colon tumors and 22 adjacent normal colon samples from The Cancer Genome Atlas (TCGA). The analysis led to the identification of ~200 differentially expressed lncRNAs. Validation in an independent cohort of normal colon and patient-derived colon cancer cell lines identified a novel lncRNA, lincDUSP, as a potential candidate oncogene. Knockdown of lincDUSP in patient-derived colon tumor cell lines resulted in significantly decreased cell proliferation and clonogenic potential, and increased susceptibility to apoptosis. The knockdown of lincDUSP affects the expression of ~800 genes, and NCI pathway analysis showed enrichment of DNA damage response and cell cycle control pathways. Further, identification of lincDUSP chromatin occupancy sites by ChIRP-Seq demonstrated association with genes involved in the replication-associated DNA damage response and cell cycle control. Consistent with these findings, lincDUSP knockdown in colon tumor cell lines increased both the accumulation of cells in early S-phase and γH2AX foci formation, indicating increased DNA damage response induction. Taken together, these results demonstrate a key role of lincDUSP in the regulation of important pathways in colon cancer.
Introduction: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in ...our population. Methods: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6–9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients. Results: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p<0.001), blood urea (p = 0.019) and, from day 6–9 results, serum bilirubin (p<0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6–9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment. Conclusions: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.
A highly diastereoselective intramolecular hydroamination is the key step in a modular synthesis of 2,6-disubstituted piperazines. The requisite hydroamination substrates were prepared in excellent ...yields by nucleophilic displacement of cyclic sulfamidates derived from amino acids. A variety of alkyl and aryl substituents at the 2-position were tolerated. The stereochemistry of the piperazines was determined to be trans by X-ray crystallography, which also showed the preferred conformation of the 2,6-disubstituted piperazine to be a twist-boat due to A(1,3) strain.
Herein we report an intermolecular propargylic C-H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and ...internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C-N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.
Selenium catalysis enables a general intermolecular propargylic C-H amination of alkynes. The concerted mechanism gives rise to high regioselectivity for the more electron-rich end of the alkyne and retention of the C-H propargylic stereocenter.
Abstract
Background
Genetic counselling aims to identify, and address, patient needs while facilitating informed decision-making about genetic testing and promoting empowerment and adaptation to ...genetic information. Increasing demand for cancer genetic testing and genetic counsellor workforce capacity limitations may impact the quality of genetic counselling provided. The use of a validated genetic-specific screening tool, the Genetic Psychosocial Risk Instrument (GPRI), may facilitate patient-centred genetic counselling. The aim of this study is to assess the effectiveness and implementation of using the GPRI in improving patient outcomes after genetic counselling and testing for an inherited cancer predisposition.
Methods
The PersOnalising gEneTIc Counselling (POETIC) trial is a hybrid type 2 effectiveness-implementation trial using a randomised control trial to assess the effectiveness of the GPRI in improving patient empowerment (primary outcome), while also assessing implementation from the perspective of clinicians and the healthcare service. Patients referred for a cancer risk assessment to the conjoint clinical genetics service of two metropolitan hospitals in Victoria, Australia, who meet the eligibility criteria and consent to POETIC will be randomised to the usual care or intervention group. Those in the intervention group will complete the GPRI prior to their appointment with the screening results available for the clinicians’ use during the appointment. Appointment audio recordings, clinician-reported information about the appointment, patient-reported outcome measures, and clinical data will be used to examine the effectiveness of using the GPRI. Appointment audio recordings, health economic information, and structured interviews will be used to examine the implementation of the GPRI.
Discussion
The POETIC trial takes a pragmatic approach by deploying the GPRI as an intervention in the routine clinical practice of a cancer-specific clinical genetics service that is staffed by a multidisciplinary team of genetics and oncology clinicians. Therefore, the effectiveness and implementation evidence generated from this real-world health service setting aims to optimise the relevance of the outcomes of this trial to the practice of genetic counselling while enhancing the operationalisation of the screening tool in routine practice.
Trial registration
Australian New Zealand Clinical Trials Registry registration number 12621001582842p. Date of registration: 19th November 2021.
Alcoholic hepatitis (AH) is an acute deterioration in liver function seen in the context of prolonged excessive alcohol consumption and is characterised by the rapid onset of jaundice. The diagnosis ...of AH has been controversial for many years: it is now accepted that there are clear clinical criteria which can be used to diagnose AH without the need for a liver biopsy. Corticosteroids remain the only treatment proven to be effective in reducing short-term mortality in severe AH; abstinence from alcohol is the most important factor in determining long-term survival. It is recommended a trial of corticosteroid therapy is considered only in those patients with high baseline ‘static’ scores (Glasgow Alcoholic Hepatitis score and model for end-stage liver disease). Response to corticosteroid therapy should be assessed using a ‘dynamic’ score such as the Lille score at day 7, with corticosteroids continuing only in patients with a favourable score. Infection and acute kidney injury are associated with poorer outcomes in AH. Early screening for and treatment of infection is recommended with antibiotic therapy overlapping with any subsequent corticosteroid treatment. A biomarker which predicts benefit from corticosteroids at baseline would avoid a trial of therapy to determine response. More efficacious therapeutic options for AH patients are required with N-acetylcysteine, granulocyte colony stimulating factor, faecal microbiota transplantation and routine antibiotics showing promise, but adequate controlled trials are needed to confirm efficacy. Liver transplant has an emerging role for some patients with severe AH not responding to corticosteroids and is likely to become more acceptable with improved methods of patient selection.
Summary
Background
In developed countries, hepatitis E is a porcine zoonosis caused by hepatitis E virus (HEV) genotype 3. In developing countries, hepatitis E is mainly caused by genotype 1, and ...causes increased mortality in patients with pre‐existing chronic liver disease (CLD).
Aim
To determine the role of HEV in patients with decompensated CLD.
Methods
Prospective HEV testing of 343 patients with decompensated CLD at three UK centres and Toulouse France, with follow‐up for 6 months or death. IgG seroprevalence was compared with 911 controls.
Results
11/343 patients (3.2%) had acute hepatitis E infection, and three died. There were no differences in mortality (27% vs. 26%, OR 1.1, 95% CI 0.28–4.1), age (P = 0.9), bilirubin (P = 0.5), alanine aminotransferase (P = 0.06) albumin (P = 0.5) or international normalised ratio (P = 0.6) in patients with and without hepatitis E infection. Five cases were polymerase chain reaction (PCR) positive (genotype 3). Hepatitis E was more common in Toulouse (7.9%) compared to the UK cohort (1.2%, P = 0.003). HEV IgG seroprevalence was higher in Toulouse (OR 17, 95% CI 9.2–30) and Truro (OR 2.5, 95% CI 1.4–4.6) than in Glasgow, but lower in cases, compared to controls (OR 0.59, 95% CI 0.41–0.86).
Conclusions
Hepatitis E occurs in a minority of patients with decompensated chronic liver disease. The mortality is no different to the mortality in patients without hepatitis E infection. The diagnosis can only be established by a combination of serology and PCR, the yield and utility of which vary by geographical location.
Summary
Nurses in primary health care (PHC) provide an increasing proportion of chronic disease management and preventive lifestyle advice. The databases MEDLINE, CINAHL, EMBASE and PsychINFO were ...searched and the articles were systematically reviewed for articles describing controlled adult lifestyle intervention studies delivered by a PHC nurse, in a PHC setting. Thirty‐one articles describing 28 studies were analysed by comparison group which revealed: (i) no difference of effect when the same intervention was delivered by a PHC nurse compared to other health professionals in PHC (n = 2); (ii) the provision of counselling delivered by a PHC nurse was more effective than health screening (n = 10); (iii) counselling based on behaviour change theory was more effective than the same dose of non‐behavioural counselling when at least three counselling sessions were delivered (n = 3). The evidence supports the effectiveness of lifestyle interventions delivered by nurses in PHC to affect positive changes on outcomes associated with the prevention of chronic disease including: weight, blood pressure, cholesterol, dietary and physical activity behaviours, patient satisfaction, readiness for change and quality of life. The strength of recommendations is limited by the small number of studies within each comparison group and the high risk of bias of the majority of studies.
Summary
Background
The assessment of alcoholic hepatitis remains controversial. Several scores have been developed or used for this purpose.
Aim
To study the use of the Glasgow Alcoholic Hepatitis ...Score (GAHS), the Discriminant Function (DF), Model for End‐Stage Liver Disease (MELD) and the ABIC (age, bilirubin, INR and creatinine) scores as well as scores to assess corticosteroid response in the management of alcoholic hepatitis.
Methods
A total of 182 patients were studied prospectively. The GAHS, MELD, ABIC and DF scores were recorded on admission and serially over the first week of hospital management. Treatment with corticosteroids or pentoxifylline was considered if the GAHS was ≥9.
Results
There were no differences in outcome between favourable scores as per recommended cut‐off points. Patients with a GAHS<9 had similar outcome whether their MELD, DF or ABIC scores were favourable or unfavourable. Treated patients with a GAHS≥9 had a significantly better 90‐day outcome than those who did not: 58% and 30% respectively, P = 0.01; HR 0.33 (0.14, 0.78).
Patients treated with corticosteroids who had a fall in bilirubin of 25% after a week of treatment had an improved survival: 82% compared with 44% P = 0.0005: HR 3.70 (1.77, 7.73). The Lille Score or a 25% fall in bilirubin had greater sensitivities than an early change in bilirubin level (95% and 90% compared with 58%) to assess treatment response.
Conclusions
In this single‐centre study, a GAHS ≥9 identified patients who may benefit from treatment of alcoholic hepatitis. Intention‐to‐treat randomised‐controlled trials using a GAHS ≥9 as the threshold for treatment are needed to validate these findings. Response to corticosteroids can be assessed using the Lille Score or by a 25% fall in bilirubin.
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