Citations

Abstract TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis. These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of these inflammatory circuits is unknown. To address this, we performed scRNA-seq and scATAC-seq in patients with COVID-19 with and without TET2-mutated clonal hematopoiesis reasoning that inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified metastasis-associated lung adenoma transcript 1 (MALAT1), a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic proinflammatory features of mTET2 in vivo. We also elucidate the mechanism by which mTET2 upregulate MALAT1 and describe an interaction between MALAT1 and p65, which leads to RNA “shielding” from protein phosphatase 2A dephosphorylation, thus preventing resolution of inflammatory signaling. Significance: This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 “shields” p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

Background The purpose of this study was to describe the correlates and outcomes in adults with unrepaired partial anomalous pulmonary venous return and intact atrial septum (PAPVR‐IAS). Methods and Results We identified adults with PAPVR‐IAS who received care at the Mayo Clinic, while those with unrepaired PAPVR‐IAS comprised the reference group. Clinical indices (New York Heart Association class, peak oxygen consumption, and NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide]) and echo‐derived right heart indices (right atrial [RA] volume, RA reservoir strain, right ventricular [RV] free wall strain, RV end‐diastolic area, and RV systolic pressure) were assessed at baseline and 3‐year and 5‐year follow‐up. There were 80 patients and 38 patients with unrepaired versus repaired PAPVR‐IAS, respectively. The clinical predictors of surgical repair were the number of anomalous veins, RA volume, and RV end‐diastolic area. The PAPVR‐IAS risk score, derived from these clinical predictors, was associated with surgical repair (adjusted odds ratio, 1.37 [95% CI, 1.24–1.65] per unit increase in risk score; area under the curve, 0.742). Among patients with unrepaired PAPVR‐IAS with 3‐year (n=73) and 5‐year follow‐up (n=36), there was no temporal change in clinical indices (New York Heart Association class, predicted peak oxygen consumption, and NT‐proBNP) and right heart indices (RA volume index, RA reservoir strain, RV end‐diastolic area index, RV free wall strain, and RV systolic pressure). Conclusions The PAPVR‐IAS risk score can be used to assess the odds of requiring surgical repair. Furthermore, there was no temporal deterioration in clinical and right heart indices during follow‐up in adults with unrepaired PAPVR‐IAS.

Background: The field of metabolic and bariatric surgery (MBS) is currently an expanding surgical field with constant refinements in techniques, outcomes, indications, and objectives. MBS has been effectively applied across diverse patient demographics, including varying ages, genders, body mass indexes, and comorbidity statuses. Methods: We performed a comprehensive literature review of published retrospective cohort studies, meta-analyses, systematic reviews, and literature reviews from inception to 2024, reporting outcomes of MBS using databases such as PubMed, ScienceDirect, and Springer Link. Results: MBS is a safe and efficient therapeutic option for patients with obesity and associated medical conditions (mortality rate 0.03–0.2%; complication rates 0.4–1%). The favorable safety profile of MBS in the short-, mid-, and long-term offers the potential to treat patients with obesity and type 2 diabetes mellitus, immunosuppression, chronic anticoagulation, neoplastic disease, and end-organ failure without increased morbidity and mortality. Conclusions: In conclusion, the future of MBS lies in the ongoing innovation and adapted therapeutic strategies along with the integration of a variety of other techniques for managing obesity. Careful preoperative assessments, coupled with a multidisciplinary approach, remain essential to ensure optimal surgical outcomes and patient satisfaction after MBS.

ABSTRACTIntroductionLow body weight in patients with COPD is associated with a poor prognosis and more comorbidities. However, the impact of increased body weight in patients with COPD remains controversial. The aim of this study was to explore the clinical features of overweight patients with AECOPD.MethodsIn this multicenter cross‐sectional study, a total of 647 AECOPD patients were recruited. Finally, 269 normal weight and 162 overweight patients were included. Baseline characteristics and clinical and laboratory data were collected. The least absolute shrinkage and selection operator (LASSO) regression was performed to determine potential features, which were substituted into binary logistic regression to reveal overweight‐associated clinical features. The nomogram and its associated curves were established to visualize and verify the logistic regression model.ResultsSix potential overweight‐associated variables were selected by LASSO regression. Subsequently, a binary logistic regression model identified that the rates of type 2 diabetes (T2DM) and hypertension and levels of lymphocytes (LYM)%, and alanine aminotransferase (ALT) were independent variables of overweight in AECOPD patients. The C‐index and AUC of the ROC curve of the nomogram were 0.671 and 0.666, respectively. The DCA curve revealed that the nomogram had more clinical benefits if the threshold was at a range of 0.22~0.78.ConclusionsCollectively, we revealed that T2DM and hypertension were more common, and LYM% and ALT were higher in AECOPD patients with overweight than those with normal weight. The result suggests that AECOPD patients with overweight are at risk for additional comorbidities, potentially leading to worse outcomes.

SummaryDespite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker‐directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2‐mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi‐responders, and describe distinct transcriptional characteristics and co‐occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

Abstract Background Sexual Medicine Society of North America (SMSNA) fellowships offer variable experience in sexual health domains: erectile dysfunction, Peyronie’s disease, male infertility, male hypogonadism (low testosterone), reconstruction (including male incontinence), benign prostatic hyperplasia, gender affirmation surgery, sexual mental health, and female sexual dysfunction. Aim To evaluate baseline and postbootcamp understanding and trust in these domains. Methods In 2023, 28 of 31 urologists currently enrolled in SMSNA-endorsed fellowships participated in a 3.5-day training bootcamp in Minneapolis, Minnesota. Participants were asked to complete pre- and postbootcamp surveys. The bootcamp curriculum offered American Urological Association guidelines and case-based lectures, hands-on clinical training with cadavers (penile surgery) and models (collagenase training), and interaction with industry. Outcomes Changes in knowledge, independence, and trust in performing the procedures, as well as billing issues and feedback for future bootcamps. Results Prebootcamp surveys revealed vastly varied residency experience. Reported time with an expert faculty member was greatest for benign prostatic hyperplasia and least for female sexual dysfunction, gender affirmation surgery, and low testosterone. The lowest prebootcamp confidence in performing surgery independently was for penile grafting procedures and elevating the neurovascular bundle. Postbootcamp results revealed several areas of significant improvement in confidence (P ≤ .03): intralesional injections for Peyronie’s disease, manual modeling, penile plication, penile grafting procedures, and elevating the neurovascular bundle. There was a trend for improved confidence with the insertion of inflatable (P = .05) and semirigid (P = .08) penile prostheses. Nonsignificant improvement occurred in artificial urinary sphincter surgery (P = .12). Participants graded the bootcamp very highly and requested that next year’s bootcamp have more content on female sexual dysfunction, male incontinence, and low testosterone, as well as more hands-on skills sessions and case-based lecture formats. Clinical Implications Offering a bootcamp with hands-on instruction could significantly improve urologists’ knowledge and confidence. Strengths and Limitations As the main strength, this study was the first specialized bootcamp for urologists in the subject of men’s health, taking into account hands-on and cadaver laboratories, as well as highlighting industrial and pharmaceutical products. The small sample size was the major limitation. Conclusions Current SMSNA fellows present with varied levels of experience and confidence across sexual health domains. Notable confidence improvements were seen with topics that combined didactic lectures with hands-on trainings.

Abstract Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.

AbstractIron Dextran is a widely used iron oxide compound to treat iron‐deficiency anemia patients in the clinic. Similar to other iron oxide compounds such as Ferumoxytol, it can also be used off‐label as an intravascular magnetic resonance imaging (MRI) contrast agent due to its strong iron‐induced T2 and T2* shortening effects. In this study, we seek to evaluate the feasibility of using Iron Dextran enhanced multi‐echo susceptibility weighted imaging (SWI) MRI at 7T to image arterial and venous blood vessels in the human brain. Phantom experiments were performed to measure the r2* relaxivity for Iron Dextran in blood, based on which the SWI sequence was optimized. Pre‐ and post‐infusion MR images were acquired in human subjects from which maps of arteries and veins were extracted. The post‐contrast SWI images showed enhanced susceptibility difference between blood and the surrounding tissue in both arteries and veins. Our results showed that the proposed Iron Dextran enhanced multi‐echo SWI approach allowed the visualization of blood vessels with diameters down to ~100 μm, including small blood vessels supplying and draining small brain structures such as the hippocampus. We conclude that Iron Dextran can be an alternative iron‐based MRI contrast agent for blood vessel imaging in the human brain.