"The Failing Watchman": Recurrent Left Atrial Appendage Occlusion Device (LAAOD) Thrombus After Successful Initial Implantation.

A 79-year-old female with chronic atrial fibrillation was being treated with dabigatran (Pradaxa). Pradaxa was discontinued after a significant bleeding episode. A WATCHMAN device was successfully implanted and Pradaxa was started. A transesophageal echocardiogram (TEE) 49 days later showed a 3.6×2.2 cm clot overlying the device. Pradaxa was switched to Coumadin. Subsequent TEEs showed the complete resolution of the thrombus after five months on Coumadin. Coumadin was discontinued. Six months later, TEE showed a large mobile thrombus attached to the left atrial appendage occlusion device (LAAOD). The patient's hypercoagulable workup was negative. Due to recurrent thrombotic events, she was started on apixaban (Eliquis) due to a prior history of bleeding on Coumadin. She is currently on Eliquis with no further episodes of bleeding or device thrombus.

Analysis of the effect of staple line reinforcement on leaking and bleeding after sleeve gastrectomy from the UK National Bariatric Surgery Registry.

INTRODUCTION: Sleeve gastrectomy (SG) is currently the most frequently performed procedure for obesity worldwide. Staple line reinforcement (SLR) has been suggested as a strategy to reduce the risk of staple line leak or bleeding; however, its use for SG in the United Kingdom (UK) is unknown. This study examined the effect of SLR on the development of postoperative complications from SG using a large national dataset from the UK. METHODS: Patients undergoing either primary or revision SG over 10 years from Jan 2012 to Dec 2021 were identified by the National Bariatric Surgery Registry. Comparative and logistic regression analyses were undertaken to determine the effect of SLR on staple line leak and bleeding. RESULTS: During this time, 14,231 patients underwent SG for whom there were complete data. Of these, 76.5% were female and the median age was 46 years (IQR: 36-53). The rate of surgical complications was 2.3% (n = 219/14,231). The incidence of bleeding was 1.3% (n = 179/14,231) and leak was 1.0% (n = 140/14,231). Over time, the use of SLR of any variety declined significantly from 99.7% in 2012 to 57.3% in 2021 (p < 0.001). Multivariable (adjusted) regression analysis demonstrated that neither the use of nor the type of reinforcement had any effect on the rate of bleeding or leaking. CONCLUSION: SLR for SG has declined in the UK since 2012. There were no differences in staple line leak or bleed with or without reinforcement.

Hydrophilic catheters for intermittent catheterization and occurrence of urinary tract infections. A retrospective comparative study in patients with spinal cord Injury.

BACKGROUND: Neurogenic bladder dysfunction is a major problem for spinal cord injury (SCI) patients not only due to the risk of serious complications but also because of the impact on quality of life. The main aim of this study is to compare the rate of urinary tract infection (UTI) associated with hydrophilic-coated catheters versus uncoated polyvinyl chloride (PVC) catheters among SCI patients presenting with functional neurogenic bladder sphincter disorders. METHODOLOGY: This was a retrospective cohort study from 2005 to 2020 including adult male or female patients who have an SCI at least more than 1 month ago with neurogenic bladder dysfunction and were using intermittent catheterization (single-use hydrophilic-coated or the standard-of-care polyvinyl chloride uncoated standard catheters) at least 3 times a day to maintain bladder emptying. RESULTS: A total of 1000 patients were selected and recruited through a stratified random sampling technique with 467 (47.60%) patients in the uncoated catheter arm and 524 (52.60%) in the coated catheter groups. The three outcome measures, namely: symptomatic UTI, Bacteriuria, and pyuria were significantly higher in the group using uncoated polyvinyl chloride (PVC) catheters compared to hydrophilic-coated catheters at the rate of 79.60% vs.46.60%, 81.10% vs. 64.69, and 53.57% versus 41.79% respectively. Males, elder patients, longer duration, and severity of SCI were associated with increased risk of symptomatic UTI. CONCLUSIONS: The results indicate a beneficial effect regarding clinical UTI when using hydrophilic-coated catheters in terms of fewer cases of symptomatic UTI. Bacteriuria is inevitable in patients with long-term catheterization, however, treatment should not be started unless the clinical symptoms exist. More attention should be given to the high-risk group for symptomatic UTIs.

Magnetic sphincter augmentation in the management of gastro-esophageal reflux disease: A systematic review and meta-analysis.

BACKGROUND: Magnetic sphincter augmentation (MSA) through placement of the LINX device is an alternative to fundoplication in the management of gastro-esophageal reflux disease (GERD). This systematic review and meta-analysis aimed to assess efficacy, quality of life and safety in patients that underwent MSA, with a comparison to fundoplication. METHODS: A literature search of MEDLINE, Embase, Emcare, Scopus, Web of Science and Cochrane library databases was performed for studies that reported data on outcomes of MSA, with or without a comparison group undergoing fundoplication, for GERD from January 2000 to January 2023. Meta-analysis was performed using random-effect models and between-study heterogeneity was assessed. RESULTS: Thirty-nine studies with 8,075 patients were included: 6,983 patients underwent MSA and 1,092 patients had laparoscopic fundoplication procedure. Ten of these studies (seven retrospective and three prospective) directly compared MSA with fundoplication. A higher proportion of individuals successfully discontinued proton-pump inhibitors (P<0.001; WMD 0.83; 95% CI 0.72-0.93; I2=96.8%) and had higher patient satisfaction (P<0.001; WMD 0.85; 95% CI 0.78-0.93; I2=85.2%) following MSA when compared to fundoplication. Functional outcomes were better after MSA than after fundoplication including ability to belch (P<0.001; WMD 0.96; 95% CI 0.93-0.98; I2=67.8) and emesis (P<0.001; WMD 0.92; 95% CI 0.89-0.95; I2=42.8%), and bloating (P=0.003; WMD 0.20; 95% CI 0.07-0.33; I2=97.0%). MSA had higher rates of dysphagia (P=0.001; WMD 0.41; 95% CI 0.17-0.65; I2=97.3%) when compared to fundoplication. The overall erosion and removal rate following MSA was 0.24% and 3.9% respectively, with no difference in surgical re-intervention rates between MSA and fundoplication (P=0.446; WMD 0.001; 95% CI -0.001-0.002; I2 =78.5%). CONCLUSIONS: MSA is a safe and effective procedure at reducing symptom burden of GERD and can potentially improve patient satisfaction and functional outcomes. However, randomized controlled trials directly comparing MSA with fundoplication are necessary to determine where MSA precisely fits in the management pathway of GERD.

Predicting COVID-19 outcomes with the Edmonton Obesity Staging System.

BACKGROUND: Multiple studies have demonstrated a correlation between a high body mass index and discriminatory COVID-19 outcomes. Studies appear to indicate that there is a correlation between obesity-related comorbidities and less favorable outcomes. OBJECTIVES: The primary aim of the current investigation is to conduct a thorough assessment of the correlation between BMI and comorbidities associated with obesity, and their potential impact on the severity and consequences of COVID-19 infection among patients receiving care in a tertiary healthcare setting. DESIGN: Retrospective cohort. SETTINGS: Tertiary rehabilitation center, Riyadh, Saudi Arabia. PATIENTS AND METHODS: The study included all individuals who received medical treatment and tested positive for COVID-19 by means of RT-PCR during the period from March to September 2020. COVID-19 patients were classified using Edmonton Obesity Staging System (EOSS). MAIN OUTCOME MEASURES: COVID-19-related complications, including pneumonia and cytokine release syndrome, as well as the time length to COVID-19 negativization. SAMPLE SIZE: 315 patients. RESULTS: The median (25th-75th percentiles) age of the patients was 38 (31.5-49) years old. Males outnumbered females, and 66% of patients were non-Saudis. Forty-eight patients (15.2%) had obesity class I, whereas 13 patients (4.1%) had class II. Thirty-two patients (10.2%) were classified as EOSS stage 1, 105 patients (33.3%) were classified as EOSS stage 2, and 25 patients (7.9%) were assigned to EOSS stage 3. Males predominated in EOSS stages 1 and 2, whereas females predominated in stage 3. In EOSS stage 3, 52% of cases had moderate severity and 48% had severe illness. CONCLUSIONS: EOSS distinguishes the COVID-19 risks of poor outcomes beyond BMI. Patients who were overweight or obese but remained in the stage 1 of the EOSS had a lower risk of a poor COVID-19 outome than normal-weight patients. The health status of obese patients is a more precise indicator of the progression of COVID-19 during hospitalization than BMI alone. LIMITATIONS: Given the limited capacity of urgent care facilities to conduct a comprehensive evaluation of comorbidities and other relevant outcomes in all patients, it is plausible that certain patients may have been erroneously classified with an EOSS stage 2 diagnosis, when in fact they ought to have been assigned a stage 3 diagnosis.

Using the Power Wheel as a transformative tool to promote equity through spaces and places of patient engagement.

BACKGROUND: Patient engagement is the active collaboration between patient partners and health system partners towards a goal of making decisions that centre patient needs-thus improving experiences of care, and overall effectiveness of health services in alignment with the Quintuple Aim. An important but challenging aspect of patient engagement is including diverse perspectives particularly those experiencing health inequities. When such populations are excluded from decision-making in health policy, practice and research, we risk creating a healthcare ecosystem that reinforces structural marginalisation and perpetuates health inequities. APPROACH: Despite the growing body of literature on knowledge coproduction, few have addressed the role of power relations in patient engagement and offered actionable steps for engaging diverse patients in an inclusive way with a goal of improving health equity. To fill this knowledge gap, we draw on theoretical concepts of power, our own experience codesigning a novel model of patient engagement that is equity promoting, Equity Mobilizing Partnerships in Community, and extensive experience as patient partners engaged across the healthcare ecosystem. We introduce readers to a new conceptual tool, the Power Wheel, that can be used to analyse the interspersion of power in the places and spaces of patient engagement. CONCLUSION: As a tool for ongoing praxis (reflection +action), the Power Wheel can be used to report, reflect and resolve power asymmetries in patient-partnered projects, thereby increasing transparency and illuminating opportunities for equitable transformation and social inclusion so that health services can meet the needs and priorities of all people.

Retinal complications post posterior chamber phakic intraocular lens implantation at a tertiary eye hospital in the Eastern Province of Saudi Arabia.

PURPOSE: Phakic intraocular lenses treat higher degrees of myopia not possible previously with conventional refractive surgery. The aim of this study is to report the incidence and risk factors of retinal complications after posterior chamber PIOL implantation and assess the differences in biometric parameters between patients who developed such complications versus those who did not. METHODS: This retrospective study recruited 514 patients who underwent ICL implantation to correct myopia at a tertiary eye hospital center in the Eastern province of Saudi Arabia. Follow up period was at least one year. Medical records of the patients were reviewed to obtain the required data. Associations between respondents' characteristics and retinal complications were evaluated using the Chi-squared test. RESULTS: The mean (SD) age was 27.7 (± 6.5) years ranging from 18 to 47. Laser treatment was performed in 14 cases (2.7%). Retinal complications occurred in six cases (1.2%). The risk of retinal complication was significantly higher among patients with high axial length (OR = 1.3, 95% CI 1.2, 1.4) and patients with high pre-spherical equivalent before ICL (OR = 1.09, 95% CI 1.03, 1.4). CONCLUSION: Patients with higher axial length and higher pre-spherical equivalent before ICL implantation are at high risk of retinal complications.

Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.

Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± 5.3/9.3 ± 5.4), a medulloblastoma (ages 6.9 ± 3.5/6.5 ± 4.4), or a pilocytic astrocytoma (8.0 ± 3.6/6.3 ± 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1H-MRS may have better diagnostic performance for paediatric brain tumours.

Survey of Canadian Physician Use of Botulinum Toxin A (BoNT-A) for Paratonia: Real World Insights.

Paratonia is a form of hypertonia characterized by an inability to relax muscles in the setting of cognitive impairment. Paratonia results in pain, refusal of care, and caregiver burden. We sent surveys to 67 Canadian physiatrists and neurologists regarding their experience treating paratonia with botulinum toxin A (BoNT-A). Twenty-seven survey respondents were included in the analysis. Thirteen percent of survey respondents treating paratonia with BoNT-A reported a significant clinically relevant improvement; 74% endorsed a moderately clinically relevant improvement; 13% endorsed a slight clinically relevant improvement. Ninety percent of survey respondents endorsed significant barriers in treating paratonia with BoNT-A.

Recent trends and advances in novel formulations as an armament in Bcl-2/Bax targeted breast cancer.

Breast cancer (BC) remains a significant health burden worldwide, necessitating the development of innovative therapeutic strategies. The B-cell lymphoma 2 (Bcl-2) family proteins, Bcl-2 and Bax, play a crucial role in regulating apoptosis and thus are promising targets for BC therapy. We focus on the recent advancements in novel formulations that specifically target Bcl-2/Bax pathway to combat BC. It provides an overview on biological functions of Bcl-2/Bax in apoptosis regulation, emphasizing their significance in pathogenesis and progression of the disease while covering the numerous therapeutic approaches aimed at modulating the Bcl-2/Bax pathway, including small-molecule inhibitors, peptides, gene-based therapies and other repurposed drugs harboured onto cutting-edge technologies and nanocarrier systems employed to enhance the targeted delivery of Bcl-2/Bax inhibitors tumor cells. These advanced formulations aim to improve therapeutic efficacy, minimize off-target effects, and overcome drug resistance, offering promising prospects in its treatment. In conclusion, it illuminates the diverse and evolving landscape of novel formulations as an essential armament in targeting these proteins while bridging and unravelling the obscurity of Bcl-2/Bax pathway-targeted drug delivery systems which are presently in their nascent stages of exploration for BC therapy which can benefit researchers, clinicians, and pharmaceutical scientists.

Characterization of seizures and EEG findings in creatine transporter deficiency due to SLC6A8 mutation.

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD. Eighteen study participants (SP) underwent video-EEG, and seven had follow-up EEG recordings. Seizures typically occurred by age of 2 years. Thirteen (65%) had non-febrile seizures, requiring anti-seizure medications in nine. Four had febrile seizures. Seizures were bilateral tonic-clonic in 7 SP and focal impaired awareness in 5 SP; often responding to 1 to 2 antiseizure medications. EEG showed slowing in 5 SP, beta activity in 6 SP, and focal/multifocal, and/or generalized epileptiform activity in 9 SP. Follow-up EEGs in 7 SP showed emergence of epileptiform activity in 1 SP, and increased activity in 2 SP. In conclusion, seizures were frequent in our cohort but tended to respond to antiseizure medications. Longitudinal follow up provided further insight into emergence of seizures and EEG abnormalities soliciting future studies with long term follow up. Biomarkers of epileptogenicity in CTD are needed to predict seizures in this population.

Implementation of a novel thoracostomy tube trainer with real-time feedback.

Objectives: Simulation-based training leads to improved clinical performance but may be influenced by quality and frequency of training. Within simulation training, chest tube insertion remains a challenge as one of the main pitfalls of insertion is a controlled pleural entry. This study evaluates the efficacy of a novel training model with real-time pressure monitoring, the average force to pleural entry in a model and the utility of audio and visual feedback. Methods: This proprietary training model comprised a modified Kelly clamp device with three force sensors at the index finger (sensor 1) and two finger loops (sensors 2 and 3), and a manikin with a replaceable chest wall pad. Standard force values (Newtons (N)) were obtained by experts; expert data revealed that 3-5 s was an acceptable time range to complete the chest tube insertion. Participant level ranged from Post-graduate Year (PGY)-1 to PGY-6 with 13 total participants. Each individual was provided an introduction to the procedure and chest tube trainer. Force (N) and time (ms) measurements were obtained from entry through dermis to pleural space puncture. A significant pressure drop suggested puncturing through the chest wall (completion of the procedure). Results: Force data were captured during each phase of the procedure-linear, plateau, and drop. Linear phase (~3000 ms) was from start of procedure to point of maximum force (<30 N). Plateau phase was from maximum force to just before a drop in pressure. Drop phase was a drop in pressure by 5+ N in a span of 150 ms signaling completion of procedure. All participants were able to complete the task successfully. Force for pleural entry ranged from 17 N to 30 N; time to pleural entry ranged from 7500 to 15 000 ms. There was variability in use of all three sensors. All participants used the index sensor, however there was variability in the use of the loop sensors depending on the handedness of the participant. Left-handed users relied more on sensors 1 and 3 while right-handed users relied more on sensors 1 and 2. Given this variability, only force measurements from sensor 1 were used for assessment. Conclusions: This novel force-sensing chest tube trainer with continuous pressuring monitoring has a wide range of applications in simulation-based training of emergency surgical tasks. Next steps include evaluating its impact on accuracy and efficiency. Applications of real-time feedback measuring force are broad, including vascular access, trocar placement and other common procedures. Level of evidence: Level IV, prospective study.

Prevalence of Multidrug-Resistant and ESBL-Producing Bacterial Pathogens in Patients with Chronic Wound Infections and Spinal Cord Injury Admitted to a Tertiary Care Rehabilitation Hospital.

A pressure ulcer is defined as a skin lesion of ischemic origin, a condition that contributes to morbidity and mortality in patients with spinal cord injuries. The most common complication of ulcers is a bacterial infection. Antimicrobial therapy should be selected with caution for spinal cord injury patients since they have a high risk of developing multidrug-resistant (MDR) infections. The aim of this study was to determine the prevalence of different bacterial pathogens in patients with pressure ulcers admitted with spinal cord injuries. This was a retrospective single-center study that included adult patients aged 18 years and above, admitted with chronic pressure wounds after a spinal cord injury requiring hospitalization between 2015 and 2021. A total of 203 spinal cord injury patients with pressure ulcers were included in the study. Ulcers were commonly infected by Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, and they were mostly located in the sacral and gluteal areas. More than half of the bacteria isolated from patients were sensitive to commonly tested antibiotics, while 10% were either MDR- or pan-drug-resistant organisms. Of the MDR bacterial isolates, 25.61% were methicillin-resistant S. aureus, and 17.73% were extended-spectrum beta-lactamase Enterobacteriaceae. The most prevalent bacteria in pressure ulcers of spinal cord injury patients were S. aureus. Other antibiotic-resistant organisms were also isolated from the wounds.

A Rare Case of Therapy-Related B-cell Acute Lymphoblastic Leukemia Arising From Acute Myeloid Leukemia.

Therapy-related acute lymphoblastic leukemia (t-ALL) is a rare potential complication of chemotherapy. We describe the case of a 47-year-old male patient who was originally diagnosed with t(8;21) positive acute myeloid leukemia (AML) in 2019, received chemotherapy, achieved remission, and was disease-free for the next two years. During a routine follow-up in 2022, he was found to have developed subclinical pancytopenia, and further studies indicated a diagnosis of pH-negative, near-tetraploid B-cell acute lymphoblastic leukemia (B-ALL) that was positive for a Tier 1 TP53 mutation, consistent with t-ALL. The patient had a prolonged treatment course complicated by social factors, such as the impact of both disease and treatment on his ability to work enough to make a living and live life with the quality he desired. The patient elected to pause treatment and resume it at a later date, after which, unfortunately, significant disease progression occurred and the patient died from complicating neutropenic sepsis and variceal bleeding. This case illustrates the challenges of managing social circumstances and patient goals in the setting of medically necessary but potentially harsh treatment courses. Given the aggressive nature of t-ALL and its overall poor prognosis, goals of care must be re-evaluated and discussed often to ensure alignment of therapy with a patient's wishes.

Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the digestive tract with increasing prevalence globally. Although venous thromboembolism (VTE) is a major complication in IBD patients, it is often underappreciated with limited tools for risk stratification. AIM: To estimate the proportion of VTE among IBD patients and assess genetic risk factors (monogenic and polygenic) for VTE. METHODS: Incident VTE was followed for 8465 IBD patients in the UK Biobank (UKB). The associations of VTE with F5 factor V leiden (FVL) mutation, F2 G20210A prothrombin gene mutation (PGM), and polygenic score (PGS003332) were tested using Cox hazards regression analysis, adjusting for age at IBD diagnosis, gender, and genetic background (top 10 principal components). The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve (AUC). RESULTS: The overall proportion of incident VTE was 4.70% in IBD patients and was similar for CD (4.46%), UC (4.49%), and unclassified (6.42%), and comparable to that of cancer patients (4.66%) who are well-known at increased risk for VTE. Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers, hazard ratio (HR) was 1.94, 95% confidence interval (CI): 1.42-2.65. In contrast, patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores (middle 8 deciles), HR was 2.06 (95%CI: 1.57-2.71). The AUC for differentiating VTE diagnosis was 0.64 (95%CI: 0.61-0.67), 0.68 (95%CI: 0.66-0.71), and 0.69 (95%CI: 0.66-0.71), respectively, for F5/F2 mutation carriers, PGS, and combined. CONCLUSION: Similar to cancer patients, VTE complications are common in IBD patients. PGS provides more informative risk information than F5/F2 mutations (FVL and PGM) for personalized thromboprophylaxis.

Control of TGFß signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12.

Transforming growth factor ß (TGFß) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFß signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFß signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFß signalling in multiple models. Interestingly, TRIP12 control of TGFß signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFß signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFß signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFß mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFß induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFß signalling in health and disease.

Epigenetic inhibitors and their role in cancer therapy.

Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy.