Citations

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

Abstract Extrachromosomal DNA (ecDNA) drives the evolution of cancer cells by conferring survival advantages over normal cells. However, the functional importance of ecDNA replication and maintenance is yet to be evaluated, and the molecular components that contributed to these processes remain largely unknown. Here, using CRISPR-C (circularization of genes and chromosomes by CRISPR) technology and synthetic circular DNA mimicking ecDNA identified in tumors, we generated ecDNA-positive (ecDNA+) cell models. Using these models, we identified the proteins involved in ecDNA replication and maintenance and found DNA damage response (DDR)-related pathways were significantly enriched. We further demonstrated that ecDNA replication led to increased DDR and genome instability and DDR was also essential for ecDNA maintenance, consistent with observations that ecDNA+ tumors exhibited higher DDR scores than ecDNA-negative (ecDNA–) tumors in patients. ATM, MDC1, and CHK2, but not ATR, were activated in ecDNA+ cells compared to ecDNA– cells. Moreover, ecDNA+ cells were more sensitive to ATM and CHK2 inhibition. We further found that type II topoisomerase TOP2B and DNA ligase III (LIG3) were critical regulators for ecDNA replication and maintenance and related DDR. In summary, our findings of the reciprocal interactions between ecDNA and DDR provide new insights into detection and therapy for ecDNA+ tumors.

SummaryPrevious studies have shown that orally administered epidermal growth factor (EGF) enhances neonatal intestinal growth and that it may be absorbed in the intestine and bound by other organs. This study investigated whether the ingestion of EGF would be associated with growth of nonintestinal organs. In short‐term studies, 87 newborn rat pups were fed artificial formula containing various concentrations of EGF for 39 h. In long‐term studies, suckling newborn pups were fed EGF or an equal volume of distilled water for 5 days. The pups fed formula containing EGF for 39 h had a significant increase in hepatic incorporation of [3H]thymidine into DNA compared with pups not fed EGF. By 5 days of age, 13 pups fed EGF had heavier livers that contained more DNA and RNA compared with 14 control pups. Moreover, EGF‐fed pups had heavier hearts and kidneys than pups fed no EGF. These data suggested that ingestion of EGF is associated with the growth of nonintestinal organs.

Background: The outcomes of leadless pacemaker (LP) implantation after transvenous lead removal (TLR) of infected cardiac implantable electronic devices (CIED) are not well-established. Objective: This study sought to describe the outcomes of LP implantation following TLR of infected CIED. Method: We conducted a literature search using PubMed and Embase for a combination of term including leadless pacemaker implantation, transvenous lead extraction, transvenous lead removal , transvenous lead explant , infected cardiac implantable electronic device . The inclusion criterion was LP implantation after TLR of infected CIED. The exclusion criterion was TLR for non-infectious reason. Study end-points were procedural complications and LP infection. Result: Of 132 publications reviewed, 13 studies with a total of 253 patients (74 ± 14 years of age, 69% males) were included. Amongst, 56.8% had systemic CIED infection and 43.2% had isolated pocket infection. Staphylococcus Aureus was the most common causative organism in 33% of the reported patients. Of 253 patients included, 105 patients (41.5%) underwent concomitant LP implantation during TLR procedure, and 36 patients (14.2%) had transvenous pacing as a bridge from TLR to LP implantation. During the LP implantation, 1 patient (0.4%) had an intra-procedural complication requiring sternotomy. Post-LP implantation, 2 patients (0.8%) developed groin hematoma, 2 patients (0.8%) developed femoral arteriovenous fistula, and 1 patient (0.4%) developed pericardial effusion requiring pericardiocentesis. During a mean follow-up of 11.3 ±10.6 months, 3 patients (1.2%) developed pacemaker syndrome, 1 patient (0.4%) developed acute on chronic heart failure exacerbation, and only 1 patient (0.4%) developed LP-related infection requiring LP retrieval. Conclusion: This study suggests that LP implant is feasible and safe post-removal of infected CIED with cumulative adverse events at 4% and a reinfection rate of 0.4%.

Background: While cardiac involvement in sarcoidosis could be significant, data assessing geographical disparities in cardiovascular deaths (CVDs) among patients with sarcoidosis are limited. Objective: This study aims to determine the mortality attributed to CVDs with comorbid sarcoidosis in different geographic locations in the United States. Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database and performed serial cross-sectional analyses of national death certificate data for CVDs with comorbid sarcoidosis among patients aged 25 and above. Diseases of the circulatory system (ICD-10 I00-I99) were listed as the underlying cause of death, and sarcoidosis (ICD-10 D86) as contributing cause of death. We calculated age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and compared the mortality among census regions and states. Results: In the 22-year study period, 5,630 CVDs with comorbid sarcoidosis in the United States were identified between 1999 and 2020. The South region had the highest AAMRs for CVDs with comorbid sarcoidosis (1.32 [95% CI, 1.26-1.37] per 1,000,000 individuals), followed by Northeast region (1.25 [95% CI, 1.18-1.32] per 1,000,000 individuals), Midwest region (1.24 [95% CI, 1.17-1.30] per 1,000,000 individuals), and West Region (0.92 [95% CI, 0.86-0.98] per 1,000,000 individuals). The AAMRs for CVDs with comorbid sarcoidosis were between 0.57 [95% CI, 0.43-0.75] per 1,000,000 individuals and 1.96 [95% CI, 1.73-2.19] per 1,000,000 individuals throughout the States, except Maryland and the District of Columbia, which recorded 2.79 [95% CI, 2.44-3.14] and 6.01 [95% CI, 4.44-7.94], respectively. Conclusion: The South region, particularly Maryland recorded the highest CVDs in sarcoidosis. Geographical disparities observed in CVDs with comorbid sarcoidosis highlight the need to improve public health measures at state-level.

Background: Sarcoidosis is a multisystem inflammatory disease that could result in debilitating cardiac manifestations. Despites, data on the cardiovascular deaths (CVDs) among patients with sarcoidosis are limited. Objective: This study sought to determine the longitudinal trends in mortality attributed to CVDs with comorbid sarcoidosis by age, sex, and race in the United States. Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database and performed serial cross-sectional analyses of national death certificate data for CVDs with comorbid sarcoidosis among patients aged 25 and above. Diseases of the circulatory system (ICD-10 I00-I99) were listed as the underlying cause of death, and sarcoidosis (ICD-10 D86) as contributing cause of death. We calculated age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and determined the trends over time by estimating the annual percent change using the Joinpoint Regression Program. Results: In the 22-year study period, 5,630 CVDs with comorbid sarcoidosis in the United States were identified between 1999 and 2020. The AAMRs from CVDs with comorbid sarcoidosis increased from 1.03 (95% CI, 0.88-1.17) in 1999 to 1.38 (95% CI, 1.24-1.52) in 2020. Overall, women recorded a higher AAMRs compared to men (1.25 [95% CI, 1.21-1.30] vs. 1.10 [95% CI, 1.06-1.15]). Black individuals had higher AAMRs than White individuals (5.17 [95% CI, 4.97-5.37] vs. 0.68 [95% CI, 0.66-0.71]). A higher percentage of CVDs with comorbid sarcoidosis was seen in the age groups of 55-64 in men (24.68%) and 65-74 in women (22.62%). Conclusion: The CVDs in sarcoidosis have increased over the last two decades, with disparities seen in women and Black individuals. Most CVDs with comorbid sarcoidosis occurred at a younger age compared to general population. This highlights the importance of early screening for cardiovascular diseases in sarcoidosis individuals.

Background: Catheter ablation for ventricular tachycardia (VT) has been increasingly performed. While it is estimated that 42% of adults in the United States are obese, the impact of obesity on VT ablation procedures remains unclear. Objective: This study aimed to evaluate the procedural outcomes and 30-day readmission among non-obese and obese patients who underwent catheter ablation of VT. Method: Using the Nationwide Readmissions Database, our study included patients aged 18 years or older who underwent catheter ablation for VT between 2017 and 2020. The study cohort was stratified into non-obese (BMI < 30kg/m 2 ) and obese (BMI ≥ 30kg/m 2 ). The in-hospital procedural outcome and 30-day readmission were analyzed between these groups. Results: Our study included a total of 835 obese patients (19.7%) and 3393 non-obese patients (80.3%). Obese group had a higher rate of prolonged length of stay (>7 days) (37.6% vs 31.2%, p<0.01) and a higher cost of hospitalization ($39 983 vs $37 015, p<0.01). Overall, there were no significant differences in early mortality (4.5% vs 3.8%, p=0.45). Apart from increased vascular complications in the obese group (1.8% vs 0.9%, p=0.03), there were no significant differences in other procedural complications between both groups. There were no significant differences in 30-day readmission rates between obese and non-obese groups (15.5% vs 14.1%, p=0.38). Additional analysis performed in the obese group revealed a non-significant decreasing trend in early mortality rate post-procedurally (5.4% to 4.8%, P trend = 0.66). On multivariable analysis, heart failure was associated with a higher risk of 30-day readmission in obese patients (OR: 2.00; 95% CI: 1.01-3.99; p=0.05). Conclusion: Our study suggests that catheter ablation for VT can be performed relatively safely in obese patients without significant differences in 30-day mortality and readmission outcomes. Patients should not be excluded from VT ablation on the basis of obesity.

Objective This pilot study seeks to identify serum immune signatures across clinical stages of patients with chronic pancreatitis (CP). Methods We performed a cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies-study. CP subjects were categorised into three clinical stages based on the presence/absence of metabolic complications: (1) CP with no diabetes and exocrine pancreatic dysfunction (EPD), (2) CP with either diabetes or EPD, and (3) CP with diabetes and EPD. Blinded samples were analysed using an 80-plex Luminex assay of cytokines/chemokines/adhesion molecules. Group and pairwise comparisons were performed to characterise immune signatures across CP subgroups. Results A total of 135 CP subjects (evenly distributed between clinical stages) and 50 controls were studied. Interleukin-6 (IL-6), interleukin-8 (IL-8), and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in CP subjects compared to controls. The levels of IL-6 and IL-8 increased with advancing disease stages, with the highest levels observed in CP with diabetes and EPD (clinical stage 3). Furthermore, hepatocyte growth factor and macrophage-derived chemokine were significantly increased in clinical stage 3 compared to controls. Conclusion Our study reveals a progressive elevation in pro-inflammatory cytokines and chemokines with advancing clinical stages of CP. These findings indicate potential targets for the development of disease-modifying interventions.