Characterizing the Role of Thymine DNA Glycosylase in Transcriptional Regulation and Cancer In Vivo

Cytosine methylation (5mC) is essential for transcriptional control and genomic stability and is often used as a prognostic marker in cancer. Although 5mC has long been considered a relatively stable epigenetic mark, recent studies have demonstrated that it can be reversed enzymatically by TET proteins which oxidize 5mC into 5-hydroxymethylcytosine (5-hmC), and then to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5caC). This mechanism is known as active DNA demethylation and the base excision repair enzyme Thymine DNA Glycosylase (TDG) plays an essential role in this process by removing 5-fC and 5-caC which are subsequently replaced by the unmethylated cytosine. Importantly, homozygous loss of TDG in mice causes embryonic lethality and the observed defects are consistent with a central role for TDG in active demethylation and protein scaffolding events. I hypothesize that the dual catalytic and protein scaffolding activities of TDG are essential for gene transcription and that TDG functions as a tumor suppressor in vivo by maintaining epigenetic stability in cells. In this study, I investigated the regulation of Hypermethylated in Cancer 1 (Hic1) tumor suppressor to demonstrate that the dual catalytic and scaffolding activities of TDG are essential for gene transcription of HIC1. In addition, I developed a conditional TDG knockout mouse model to determine the role of TDG in development. Hic1 transcription involves a transient accumulation of 5fC/5caC metabolites and the recruitment of an RAR/RXR complex, both of which were found to be TDG dependent. Tdg deletion in vivo causes Hic1 silencing via promoter DNA hypermethylation. In addition, a loss of TDG in adult mice predisposes them to a high prevalence of hepatocellular carcinoma (HCC), independent of cirrhosis or fibrosis. Surprisingly, HCC occurred predominantly in male mice, which also showed increased obesity compared to age matched controls. RNAseq analysis of livers from TDG deleted mice showed downregulation of several metabolism relevant genes. These findings are consistent with an onset of HCC via the non-alcoholic fatty liver pathway. Collectively, this study shows that the dual catalytic and scaffolding activities of TDG are required in gene transcription events, and provides the first evidence of TDG as a tumor suppressor of liver cancers

In vitro antioxidant and antibacterial activity of twenty-one Northern Ontario medicinal plants

Aboriginal communities in the northern Ontario region utilize an abundance of locally grown medicinal plants. However, no prior documentation or phytochemical studies on the northern Ontario medicinal plants existed in literature. This prompted me to exploit the ethnobotanical resources in this region towards the study of antibacterial bioactivity and alleviation of oxidative stress. Oxidative stress plays a fundamental role in the pathogenesis of many major human illnesses, such as cancer, cardiovascular diseases, diabetes and Alzheimer’s syndrome. Also, infectious diseases are a major concern in our society due to the advent of multiple drug resistant strains of bacteria that cause millions of mortalities worldwide. From the accumulated list of 48 northern Ontario medicinal plants, I selected 21 plants based on their documented anticancer, antibacterial, antioxidant, antidiarrheal and anti-inflammatory properties. These plants were separated into leaf, flower, stem and root tissues and extracted with ethanol. In total, 43 extracts were assayed for antioxidant and antibacterial activity in this study. The antioxidant activity was evaluated through the DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt), ORAC (Oxygen radical absorption capacity), and EC50 (half maximal effective concentration) assays. The total phenolic content of medicinal plants was also determined. The antibacterial activity was determined through the hole-plate diffusion and minimum inhibitory concentration (MIC) assays on Bacillus cereus, Escherichia coli, Micrococcus luteus, Mycobacterium avium subsp. avium, Paenibacillus alvei and Aeromonas caviae bacteria. The crude extract was fractionated through manual liquid chromatography (LC) into five fractions of varying polarity using a mixture of hexane: ethyl acetate: methanol solvents and assayed for inhibitory activity in the MIC assay. Also, a few plants were shortlisted and studied for more detailed antibacterial activity through minimum bactericidal concentration (MBC) and time-kill analyses. In the antioxidant assays, all plant extracts exhibit some level of activity, however, a few were exceptional. The extracts of Cornus canadensis, Ledum palustre, Prunella vulgaris, Arctostaphylos uva-ursi, and Apocynum androsaemifolium L. from the Cornaceae, Lamiaceae, Ericaceae and Apocynaceae families, respectively, display the highest antioxidant activity and total phenolic contents. In the antibacterial assays, plants from the Asteraceae, Apocynaceae, Cornaceae and Ericaceae families display the highest activity. Particularly, the leaf and/ or flower extracts of Xanthium strumarium, Anaphalis margaritacea, Arctostaphylos uva-ursi, Apocynum androsaemifolium L., Cornus canadensis, Solidago canadensis and Grindelia squarrosa exhibit high inhibition diameters and low MIC values. Also, for the majority of extracts, an increase in bioactivity was observed in the medium polarity LC fraction, relative to the crude. Particularly, the medium polarity fraction of Anap. margaritacea flower exhibits MIC values in the range of 0.08 -1.25 mg/ml against all six bacteria tested. The crude extract of Anaphalis margaritacea flower also displays MBC values in the range of 0.16 - 5 mg/ml against A. caviae, M. luteus, P. alvei and B. cereus bacterium and demonstrates complete extermination within eight hours of incubation. Overall, this investigation provides evidence for the application of these medicinal plants towards the treatment of infectious and oxidative stress related diseases in Native Aboriginal communities

Clinical Evaluation of Pit and Fissure Sealants Placed by Undergraduate Dental Students in 5-15 Years-old Children in Iraq

Objective: To clinically evaluate the retention and marginal discoloration of pit and fissure sealants applied to primary and permanent teeth. Material and Methods: The study population encompassed of 5-15 years- old children. After consenting, a light-curing sealant was applied to etched pits and fissures of occlusal surfaces of selected sound teeth. The retention rate and marginal discoloration were assessed, 3 months after application of the sealants based on the criteria proposed by Simonsen’s criteria (total retention: score 0, partial loss: score 1, and total loss: score 2). Each tooth was considered as an independent sample during analysis. Results: The achieved sample size was 43 children aged 5-15 years (mean age=10.0 years). Therefore, data of 100 teeth from 43 children were used for the final analysis. The percentage of completely retained sealants (59%) was higher than the percentage of partially retained sealants (23%) and completely missing sealants (18%) after 3 months follow up. Out of 100 sealed teeth, 60% were either had marginal discoloration or completely missing. Using the Mann-Whitney test, there was a statistically significant difference (p<0.05) between primary and permanent teeth in terms of retention. However, there was no statistical difference (p>0.05) between upper and lower teeth in terms of retention. Conclusion: The success rate of fissure sealants after 3 months follow-up was satisfactory

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.Peer reviewe

IPA Transcription of Bengali Texts

The International Phonetic Alphabet (IPA) serves to systematize phonemes in language, enabling precise textual representation of pronunciation. In Bengali phonology and phonetics, ongoing scholarly deliberations persist concerning the IPA standard and core Bengali phonemes. This work examines prior research, identifies current and potential issues, and suggests a framework for a Bengali IPA standard, facilitating linguistic analysis and NLP resource creation and downstream technology development. In this work, we present a comprehensive study of Bengali IPA transcription and introduce a novel IPA transcription framework incorporating a novel dataset with DL-based benchmarks

Nursing And Healthcare Administration Roles With The Respiratory Therapist, Medicine, Anesthesia And Radiology Team In ICU Setting

Interprofessional rounds in the intensive care unit (ICU) facilitate scheduled meetings among diverse healthcare professionals to evaluate and analyze clinical information and formulate concise treatment plans for critically ill patients. Implementing a systematic approach to rounding enables each member of the healthcare team to focus on their specific objectives, challenges, and worries. Furthermore, they provide specialist input to the daily care plan to minimize its implications, which is crucial in the management of critically ill patients. A novel quality management (QM) effort has been introduced in an intensive care unit (ICU) to enhance the administration of radiological tests. During regular multidisciplinary conferences (MDCs), radiologists and ICU physicians conduct a thorough reassessment of recent examinations. Additionally, the objectives encompass reducing negative events, enhancing patient contentment, shortening hospital stays, and lowering mortality rates. This issue is especially arduous in critical care units, as these wards admit patients who are severely unwell, have complex medical conditions, and have the worst prognoses. By implementing interprofessional rounds and adopting a collaborative team-based approach, patient outcomes can be maximized

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention