UT Southwestern Medical Center Research Articles

RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and intestinal inflammation.

Abstract Th17 cells that produce IL-17 are pathogenic in many human diseases, including inflammatory bowel disease (IBD), but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. We have found that Raftlin1, a lipid raft protein, is specifically upregulated in and forms a complex with RORγt via its conserved LLNSL motif in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex in Raftlin1 ΔLLNSLknock-in mice resulted in attenuated pathogenic Th17 cells elicited by Citrobacter rodentium; however, there was no effect on nonpathogenic Th17 cells induced by commensal segmented filamentous bacteria (SFB). Mechanistically, we found that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a fundamental mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for new therapeutic strategies to dampen Th17-mediated inflammatory diseases. This work was supported by funds from the National Institutes of Health (R01-DK115668, R01-AI155786) and Cancer Prevention Research Institute of Texas (RP190527) and a stimulus grant from the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center.

Pak2-mediated phosphorylation promotes RORγt ubiquitination and inhibits colonic inflammation

Abstract Dysregulated Interleukin (IL)-17 expression and its downstream signaling is strongly linked to inflammatory bowel diseases (IBD). However, the molecular mechanisms by which the function of RORγt, the transcription factor of IL-17, is regulated remains elusive, which is absolutely necessary to develop advanced strategies to inhibit IL-17-mediated inflammation. By mass spectrometry-based approach, we have identified that Pak2, a Ser/Thr kinase, directly associates with RORγt. Pak2 recognizes a conserved KRLS motif within RORγt and phosphorylated the Serine (S) 316 within this motif. Genetic deletion of Pak2 in Th17 cells resulted in reduced RORγt phosphorylation, increased IL-17 expression and severe colitis upon adoptive transfer to Rag1 −/−mice. Similarly, reconstitution of RORγt-S316A mutant in Rorc −/−Th17 cells resulted in enhanced IL-17 expression and colitis severity. Mechanistically, we demonstrate that Pak2-mediated phosphorylation causes a conformational change resulting in exposure of the ubiquitin ligase Itch interacting PPLY motif and degradation of RORγt. Thus, we have uncovered a novel mechanism by which the activity of RORγt is regulated that can be exploited therapeutically. This work was supported by funds from the National Institutes of Health (R01-DK115668 and R01-AI155786) and Cancer Prevention Research Institute of Texas (RP160577 and RP190527), a translational pilot project grant from the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center (23001045) to K.V., and R01-DK117001 to K.V. and A.L.T.

Invited Commentary: Photon-counting CT: Embracing the Change

HomeRadioGraphicsVol. 43, No. 5 Previous PhysicsInvited Commentary: Photon-counting CT: Embracing the ChangeLakshmi Ananthakrishnan Lakshmi Ananthakrishnan Author AffiliationsFrom the Department of Radiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8827.Address correspondence to the author (email: [email protected]).Lakshmi Ananthakrishnan Published Online:Apr 6 2023https://doi.org/10.1148/rg.230001MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In

Fitness Training-Associated Vertebral Artery Dissection.

1Division of Cerebrovascular Disease, Department of Neurology, ECU Health Medical Center, Greenville, NC 2Division of Cerebrovascular Disease, Department of Neurology, UT Southwestern Medical Center, Dallas, TX Address for correspondence: Nurose Karim, MD, 1910 Stonehenge Drive Apartment 23, Greenville, NC 27858; E-mail: [email protected].

Asynchronous Telemedicine Platform Associated with Decreased Migraine-Related Emergency Room and Urgent Care Use (P8-12.006)

Asynchronous Telemedicine Platform Associated with Decreased Migraine-Related Emergency Room and Urgent Care Use (P8-12.006)

Abstract 5925: Prevalence of clonal hematopoiesis in patients with monoclonal gammopathy of undetermined significance

Abstract INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of progeny derived from hematopoietic stem cells that have acquired somatic mutations at a VAF greater than 2%. CHIP manifests in 10% of patients older than 65 and is associated with an increased risk of progression to malignancies such as the MDS or AML. Although the risk factors for developing CHIP remain incompletely defined, they include prior exposure to chemotherapy and a history of smoking. Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the abnormal growth of clonal plasma cells in the bone marrow and carries a risk of 1% for progression to multiple myeloma (MM) per year. Like CHIP, it becomes more prevalent with age and is associated with smoking. Additionally, patients with MM have demonstrated an increased risk for malignancies. Thus, an examination for a correlation between CHIP and MGUS promises to reveal a link between these two pre-malignant conditions. A recent study did not demonstrate such an association, but this study was performed in a very elderly population and may not be applicable to younger patients. In this study, we aim to assess the relationship between CHIP and MGUS in a population-based cohort of MGUS patients seen at UT Southwestern Medical Center. METHODS: To evaluate an association between CHIP and MGUS, we collected bone marrow samples from 37 patients diagnosed with MGUS. We employed a hybridization capture-based next generation sequencing assay in order to detect CHIP. We identified 24 genes known to cause CHIP in adults. We also evaluated patients risk for developing MM after having been diagnosed with CHIP. RESULTS: The mean age was 68, (range 26-92). 22 patients were white, 8 were black and 3 Hispanic/Latino. 17 patients had IgG, 7 had IgA, 3 had IgM, 3 had biclonal gammopathy and 7 light-chain MGUS. We identified 18 mutations to validate the presence of CHIP in 10 (27%) patients, with the most frequent being DNMT3A (7 patients) and TET2 (5 patients). Other common mutations noted were PPM1D (2), GND1 (1), SF3B1 (1), ASXL1 in (1), and NRAS in (1). 3 out of the 10 patients harbored 2 mutations and 1 harbored 4 mutations. History of chemotherapy (n=6) and smoking (n=14) was taken into consideration to determine the relative risk of patients with MGUS developing CHIP. We found that those who had a prior history of smoking and chemotherapy displayed a higher risk of CHIP. CONCLUSION: There was no significant association between CHIP and MM progression. Our analysis showed 1 patient with CHIP progression and 2 without CHIP progression. Because the rates of CHIP and MGUS are positively correlated with characteristics like aging and a history of smoking, we expected to see high rates of CHIP in patients within our cohort. However, our data suggests that CHIP is frequent (27%) in MGUS patients, but larger future cohorts need to be evaluated to validate this association. Citation Format: Vianey Quaney, Benjamin Kroger, Aishwarya Sannareddy, Umar Khan, Fatma Kalkan, Robert H. Collins, Yazan F. Madanat, Madhuri Vusirikala, Yi Huang, Farrukh T. Awan, Praveen Ramakrishnan, Aimaz Afrough, Larry D. Anderson, Stephen S. Chung, Gurbakhash Kaur. Prevalence of clonal hematopoiesis in patients with monoclonal gammopathy of undetermined significance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5925.

The effects of aneurysmal subarachnoid hemorrhage on cerebral vessel diameter and flow velocity

BackgroundTranscranial Doppler flow velocity is used to monitor for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Generally, blood flow velocities appear inversely related to the square of vessel diameter representing local fluid dynamics. However, studies of flow velocity-diameter relationships are few, and may identify vessels for which diameter changes are better correlated with Doppler velocity. We therefore studied a large retrospective cohort with concurrent transcranial Doppler velocities and angiographic vessel diameters. MethodsThis is a single-site, retrospective, cohort study of adult patients with aneurysmal subarachnoid hemorrhage, approved by the UT Southwestern Medical Center Institutional Review Board. Study inclusion required transcranial Doppler measurements within </= 24 hours of vessel imaging. Vessels assessed were: bilateral anterior, middle, posterior cerebral arteries; internal carotid siphons; vertebral arteries; and basilar artery. Flow velocity-diameter relationships were constructed and fitted with a simple inverse power function. A greater influence of local fluid dynamics is suggested as power factors approach two. Results98 patients were included. Velocity-diameter relationships are curvilinear, and well fit by a simple inverse power function. Middle cerebral arteries showed the highest power factors (>1.1, R2>0.9). Furthermore, velocity and diameter changed (P<0.033) consistent with the signature time course of cerebral vasospasm. ConclusionsThese results suggest that middle cerebral artery velocity-diameter relationships are most influenced by local fluid dynamics, which supports these vessels as preferred endpoints in Doppler detection of cerebral vasospasm. Other vessels showed less influence of local fluid dynamics, pointing to greater role of factors outside the local vessel segment in determining flow velocity.

Abstract P2-20-15: Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity

Abstract Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity Ziyi Fu1,2, Siqi Chen3, Yueming Zhu4, Donghong Zhang4, Ping Xie3, Qiao Jiao4, Shipeng Xu1, Yifan Xue6, Xinhua Lu6, Xinxin Song7, Massimo Cristofanilli8, William J Gradishar3, Kevin Kalinsky5, Yongmei Yin2, Bin Zhang3 and Yong Wan4,5* 1Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, USA. 2Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, China 3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, USA. 4Department of Pharmacology and Chemical Biology, Winship Cancer Institute, Emory University School of Medicine, USA. 5Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, USA. 6Department of Biomedical Informatics, University of Pittsburgh School of Medicine, USA. 7Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. 8Department of Medicine, Weill Cornell Medicine, USA. ABSTRACT Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that uncontrolled elevation of CD73 levels due to its aberrant turnover is tightly correlated with poor prognosis in immune-cold triple negative breast cancers (TNBCs), which impedes the efficacy for chemotherapy and immunotherapy. We have identified TRIM21 as a E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. The immunostaining demonstrated the cytosolic colocalization between TRIM21 and CD73. Molecular mapping further identified the amino acid stretches from 340-476 on TRIM21 and residues from 176–224 on CD73 mediated the interaction between TRIM21 and CD73. Replacement of lysine 133, 208, 262 and 321 by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Moreover, TRIM21 is upregulated but CD73 is downregulated in response to IFN- secreted from activated CD8+ T cells in a feedback manner. Importantly, in preclinical animal models, diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM2hight/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a novel mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation. Citation Format: Ziyi Fu, Yueming Zhu, Kevin Kalinsky, Yong Wan. Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-15.

Document Provides Inpatient Guidelines for Medication Treatment of Opioid Use Disorder

Back to table of contents Previous article Next article Clinical & ResearchFull AccessDocument Provides Inpatient Guidelines for Medication Treatment of Opioid Use DisorderAbhisek Chandan Khandai, M.D., Josie Francois, M.D.Abhisek Chandan KhandaiSearch for more papers by this author, M.D., Josie FrancoisSearch for more papers by this author, M.D.Published Online:21 Dec 2022https://doi.org/10.1176/appi.pn.2023.01.1.39AbstractA new resource document will help strengthen psychiatrists’ capabilities to be team leaders in the treatment of hospitalized patients with opioid use disorder. This article is one of a series coordinated by APA’s Council on Consultation-Liaison Psychiatry and the Academy of Consultation-Liaison Psychiatry.The prevalence, morbidity, mortality, and costs of opioid use disorder have dramatically increased over the past 20 years. While there are several effective and evidence-based medications for opioid use disorder (MOUD), less than 20% of Americans with opioid use disorder receive MOUD. The inpatient general hospital setting represents a critical point of access to MOUD, given the significant medical comorbidities of patients with opioid use disorder and the increased time to engage patients in treatment, better monitoring capabilities, and opportunities to reduce the monetary impact of the disorder on the health care system.Psychiatrists are an integral part of the hospital treatment team. However, they are often excluded for many reasons, including stigma toward opioid use disorder, lack of consultation-liaison (C-L) psychiatry services, and discomfort with managing opioid use disorder.To help address this care gap, APA’s Council on C-L Psychiatry, in collaboration with the Council on Addiction Psychiatry, convened a multispecialty expert workgroup to prepare a resource document related to the medication treatment of patients with opioid use disorder. The workgroup discussed several barriers to medication treatment and factors limiting the involvement of psychiatrists in the treatment of opioid and other substance use disorders in the inpatient hospital setting. Among the barriers they identified were stigma associated with substance use disorders (SUD) and a knowledge gap among psychiatrists regarding SUD treatment. The workgroup then created a resource document that seeks to address these barriers and guide general psychiatrists.The document includes an overview of OUD and its management in adults, explores the pharmacology of MOUD, describes barriers to care and specialty-specific concerns, and provides approaches to reducing stigma. The resource document also compares current medications to treat patients with opioid use disorder (naltrexone, buprenorphine, and methadone), walks psychiatrists through the medications’ initiation and titration in the general hospital setting, and provides recommendations on how to transition patients taking these medications from inpatient to outpatient settings.The resource guide is designed to educate and empower psychiatrists to take a larger role in MOUD in the general hospital setting to save more lives at reduced cost. Psychiatrists are in a strong position to oversee the use of MOUD in hospital settings and are best equipped to lead MOUD treatment and reduce stigma, given our relative expertise in the area of SUDs, comorbid psychiatric illnesses, and harm reduction strategies. As such, it is important that psychiatrists stay up to date on evidence-based MOUD and work with other specialties to promote psychiatric involvement in the care of those with opioid use disorder in the general hospital setting. ■Resource Document on the Treatment of Opioid Use Disorder in the General HospitalAbhisek Chandan Khandai, M.D., is a consultation-liaison psychiatry attending at UT Southwestern Medical Center and a member of APA’s Committee on Consultation-Liaison Psychiatry.Josie Francois, M.D., is a first-year psychiatry resident at Brigham and Women’s Hospital. ISSUES NewArchived

How to effectively integrate advanced practice providers into the ED workforce.

Academic Emergency MedicineVolume 30, Issue 2 p. 154-156 INVITED COMMENTARY How to effectively integrate advanced practice providers into the ED workforce Jesse M. Pines MD, MBA, MSCE, Corresponding Author Jesse M. Pines MD, MBA, MSCE jesse.pines@gmail.com orcid.org/0000-0003-2292-3052 US Acute Care Solutions, Canton, Ohio, USA Department of Emergency Medicine, Drexel University, Philadelphia, Pennsylvania, USA Correspondence Jesse M. Pines, US Acute Care Solutions, Canton, OH 44718, USA. Email: jesse.pines@gmail.comSearch for more papers by this authorD. Mark Courtney MD, MSci, D. Mark Courtney MD, MSci orcid.org/0000-0002-0905-465X Department of Emergency Medicine, UT Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this author Jesse M. Pines MD, MBA, MSCE, Corresponding Author Jesse M. Pines MD, MBA, MSCE jesse.pines@gmail.com orcid.org/0000-0003-2292-3052 US Acute Care Solutions, Canton, Ohio, USA Department of Emergency Medicine, Drexel University, Philadelphia, Pennsylvania, USA Correspondence Jesse M. Pines, US Acute Care Solutions, Canton, OH 44718, USA. Email: jesse.pines@gmail.comSearch for more papers by this authorD. Mark Courtney MD, MSci, D. Mark Courtney MD, MSci orcid.org/0000-0002-0905-465X Department of Emergency Medicine, UT Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this author First published: 29 November 2022 https://doi.org/10.1111/acem.14633 Supervising Editor: Dr. Jeffrey Kline. A related article appears on page xxx. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume30, Issue2February 2023Pages 154-156 RelatedInformation

Prevalence of Clonal Hematopoiesis in Patients with Monoclonal Gammopathy of Undetermined Significance

INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of progeny derived from hematopoietic stem cells (HSCs) that have acquired somatic mutations at a VAF greater that 2%. CHIP manifests in 10% of patients older than 65 and is associated with an increased risk of progression to hematologic malignancies such as the myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although the risk factors for developing CHIP remain incompletely defined, they include prior exposure to chemotherapy and a history of smoking. Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the abnormal growth of clonal plasma cells in the bone marrow and carries a risk of 1% for progression to multiple myeloma (MM) per year. Like CHIP, it becomes more prevalent with age and has been associated with smoking. Additionally, patients with MM have been demonstrated to have an increased risk for myeloid malignancies. Thus, an examination for a correlation between CHIP and MGUS promises to reveal a link between these two pre-malignant conditions. However, a recent study did not demonstrate such an association, but this study was performed in a very elderly population and may not be applicable to younger patients. In this study, we aim to assess the relationship between CHIP and MGUS in a population-based cohort of MGUS patients seen at UT Southwestern Medical Center. METHODS: To evaluate an association between CHIP and MGUS, we collected bone marrow samples from 37 patients diagnosed with MGUS at UT Southwestern Medical Center. We employed a hybridization capture-based next generation sequencing assay in order to detect CHIP. We identified 24 genes known to cause CHIP in adults. We also evaluated patients' risk for developing Multiple Myeloma after having been diagnosed with CHIP. RESULTS: The mean age of MGUS patients was 68, ranging between 26-92. 17 patients had IgG, 10 had IgA, five had IgM, and five had light-chain MGUS. We identified 18 mutations to validate the presence of CHIP in 10 (27%) patients, with the most frequent being in DNMT3A and TET2 (Fig. 1). Three out of the 10 patients harbored two mutations and one patient harbored four mutations. History of chemotherapy (n=6) and smoking (n=14) was taken into consideration to determine the relative risk of patients with MGUS developing CHIP. We found that those who had a prior history of smoking and chemotherapy displayed a higher risk of acquiring CHIP (Fig. 2). 54% of patients displayed high levels of serum kappa free light chains at the time of diagnosis. CONCLUSION: There was no significant association between CHIP and MM progression. Our analysis showed one patient with CHIP progression, and two patients without CHIP progression. Because the rates of CHIP and MGUS are positively correlated with characteristics like aging and a history of smoking, we expected to see relatively high rates of CHIP in patients within our cohort. However, our data suggests that CHIP is frequent (27%) in MGUS patients, but larger future cohorts need to be evaluated to validate this association. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Shape-Sensing Robotic-Assisted Bronchoscopy with Concurrent use of Radial Endobronchial Ultrasound and Cone Beam Computed Tomography in the Evaluation of Pulmonary Lesions.

Lung nodules are a common radiographic finding. Non-surgical biopsy is recommended in patients with moderate or high pretest probability for malignancy. Shape-sensing robotic-assisted bronchoscopy (ssRAB) combined with radial endobronchial ultrasound (r-EBUS) and cone beam computed tomography (CBCT) is a new approach to sample pulmonary lesions. Limited data are available regarding the diagnostic accuracy of combined ssRAB with r-EBUS and CBCT. We conducted a retrospective analysis of the first 200 biopsy procedures of 209 lung lesions using ssRAB, r-EBUS, and CBCT at UT Southwestern Medical Center in Dallas, Texas. Outcomes were based on pathology interpretations of samples taken during ssRAB, clinical and radiographic follow-up, and/or additional sampling. The mean largest lesion dimension was 22.6 ± 13.3mm with a median of 19mm (range 7 to 73mm). The prevalence of malignancy in our data was 64.1%. The diagnostic accuracy of ssRAB combined with advanced imaging was 91.4% (CI 86.7-94.8%). Sensitivity was 87.3% (CI 80.5-92.4%) with a specificity of 98.7% (CI 92.8-100%). The negative and positive predictive values were 81.3% and 99.2%. The rate of non-diagnostic sampling was 11% (23/209 samples). The only complication was pneumothorax in 1% (2/200 procedures), with 0.5% requiring a chest tube. Our results of the combined use of ssRAB with r-EBUS and CBCT to sample pulmonary lesions suggest a high diagnostic accuracy for malignant lesions with reasonably high sensitivity and negative predictive values. The procedure is safe with a low rate of complications.

Abstract 10310: Sudden Cardiac Death in Recently Diagnosed Patients With Light-Chain Cardiac Amyloidosis

Introduction: Untreated, light-chain (AL) cardiac amyloidosis is associated with a median survival of 6-months when diagnosed in advanced stage. However, current plasma cell-targeting therapies have drastically improved end-organ function and life expectancy. Yet, a portion still die despite appropriate treatment. We hypothesize this is from sudden cardiac death (SCD). Aim: To determine the incidence of and clinical characteristics associated with 90-day SCD after diagnosis of AL amyloidosis. Methods: Clinical, electrocardiographic, imaging, treatment, and outcomes were abstracted from consecutive patients diagnosed with AL amyloidosis from 2014-2022 at UT Southwestern Medical Center. Statistics were reported as mean and standard deviation. Results: In our study cohort (N=189) patients with AL amyloidosis, 18 patients (66% male, age 65 ± 9.5 y) died by 90-days (9.5%). Of these, 14 patients died by 60-days (7.3%), and 10 patient died by 30-days (5.2%). There were 7 cardiac deaths (3.6%): including one PEA arrest (0.5%), one in-hospital cardiac arrest (0.5%) and five unwitnessed out-of-hospital cardiac arrests (2.6%). Among cardiac deaths, 3 patients had endomyocardial tissue consistent with AL. Revised Mayo Stage was 66% III, 33% IV. Six patients had at least one dose of chemotherapy with bortezomib, cyclophosphamide and dexamethasone (CyBorD), Velcade/Dexamethasone, or Daratumumab/CyBorD, and 5 had at least one full cycle. The LVEF was 48.9 ± 8.1, QTc 483 ± 50 ms, interventricular septal thickness was 1.2 cm ± 0.4 cm. CMR was obtained in 4 of 7 patients, with late gadolinium enhancement present in a diffuse pattern in 75%, average LVEDV 59 ± 9.5 mL. Mean time to death was 37.2 ± 21 days. Conclusions: Sudden cardiac death may be a significant contributor to mortality among patients with newly diagnosed AL amyloidosis. These observations warrant confirmation in larger cohorts and may identify an unmet need to enhance risk stratification for SCD in this population.

First person – Lizbeth Perez-Castro and Niranjan Venkateswaran

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Lizbeth Perez-Castro and Niranjan Venkateswaran are co-first authors on ‘ The AHR target gene scinderin activates the WNT pathway by facilitating the nuclear translocation of β-catenin’, published in JCS. Lizbeth is a PhD Student in the lab of Maralice Conacci-Sorrell at UT Southwestern Medical Center, where she is interested in cell molecular biology. Niranjan is a Research scientist in same laboratory where he is interested in understanding the role of essential amino acids in cancer.

Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants.

Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. A retrospective, cross-sectional comparison of patients from 2 tertiary referral centers-UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. A total of 196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years) were included. The main outcome measures were skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia. Compared with subjects with FPLD2, subjects with FPLD3 had significantly increased prevalence of hypertriglyceridemia (66% vs 84%) and diabetes (44% vs 72%); and had higher median fasting serum triglycerides (208 vs 255 mg/dL), and mean hemoglobin A1c (6.4% vs 7.5%). Compared with subjects with FPLD2, subjects with FPLD3 also had significantly higher mean upper limb fat (21% vs 27%) and lower limb fat (16% vs 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs 11.3 mm), calf (4 vs 6 mm), triceps (5.5 vs 7.5 mm), and biceps (4.3 vs 6.8 mm). Compared with subjects with FPLD2, subjects with FPLD3 have milder lipodystrophy but develop more severe metabolic complications, suggesting that the remaining adipose tissue in subjects with FPLD3 may be dysfunctional or those with mild metabolic disease are underrecognized.

Editorial introductions.

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned to a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Genovefa A. PapanicolaouGenovefa A. PapanicolaouDr Genovefa A. Papanicolaou is the Director of Clinical Trials in the Infectious Disease Service at Memorial Sloan Kettering Cancer Center and Professor at Weill Cornell Medical College of Cornell University in New York, USA. Dr Papanicolaou is the current Chair of the Infectious Disease special Interest Group (ID-SIG) of the American Society for Transplantation and Cellular Therapy (ASTCT). Her research focuses on viral infections after stem cell transplantation and particularly cytomegalovirus (CMV). Her areas of interest are novel therapeutics, biomarkers and personalized infection management. Dionysios NeofytosDionysios NeofytosDionysios Neofytos is an Infectious Disease specialist with expertise in infectious disease complications in patients with hematologic malignancies and bone marrow and solid organ transplant recipients. Since the completion of his training in Infectious Diseases at Thomas Jefferson University Hospital in Philadelphia, PA, USA, in 2006 he has joined the Faculty and worked as an attending physician with the Transplant Infectious Disease Services at the Johns Hopkins University in Baltimore, MD, USA, and the Memorial Sloan Kettering Cancer Center in New York, NY, USA. Since 2016, he joined the Division f Infectious Diseases at the University Hospital of Geneva, in Geneva, Switzerland. His research and area of expertise are focusing on the epidemiology, diagnosis and management of viral and invasive fungal infections in immunocompromised hosts. Trish M. PerlTrish M. PerlTrish M. Perl, MD, MSc, is the H. Ben and Isabelle T. Decherd Chair in Internal Medicine (Infectious Diseases and Geographic Medicine) at UT Southwestern Medical Center in Dallas TX, USA. Dr Perl received her Medical Degree from the University of North Carolina (Chapel Hill), USA, and a Master of Science from McGill University in Montreal, Canada. She trained in Internal Medicine at the Royal Victoria Hospital and in Infectious Diseases and Clinical Epidemiology at the University of Iowa, USA. She rose through the ranks to Professor of Medicine at Johns Hopkins University School of Medicine, USA, and Epidemiology at the Bloomberg School of Public Health and is recognized globally for her innovation and research in healthcare associated infections, antimicrobial resistance, and their transmission and prevention. As the Hospital Epidemiologist at Johns Hopkins Hospital and Health System Epidemiologist, she developed extensive practical and research experience. Internationally, she has helped with outbreak management and mitigation including SARS, MERS CoV, Ebola and consults on guideline development and strategies to prevent emerging threats in healthcare. She is actively involved in monitoring the COVID-19 pandemic and supporting the national and local response.

Should Polypills Be Used for Heart Failure With Reduced Ejection Fraction?

HomeCirculationVol. 146, No. 4Should Polypills Be Used for Heart Failure With Reduced Ejection Fraction? No AccessArticle CommentaryRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessArticle CommentaryRequest AccessFull TextShould Polypills Be Used for Heart Failure With Reduced Ejection Fraction? Ambarish Pandey, MD, MSCS, Neil Keshvani, MD and Thomas J. Wang, MD Ambarish PandeyAmbarish Pandey Correspondence to: Ambarish Pandey, MD, MSCS, Assistant Professor of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9651-3836 Division of Cardiology, Department of Medicine, UT Southwestern Medical Center, Dallas, TX. Search for more papers by this author , Neil KeshvaniNeil Keshvani https://orcid.org/0000-0001-6890-8670 Division of Cardiology, Department of Medicine, UT Southwestern Medical Center, Dallas, TX. Search for more papers by this author and Thomas J. WangThomas J. Wang https://orcid.org/0000-0003-4063-6508 Division of Cardiology, Department of Medicine, UT Southwestern Medical Center, Dallas, TX. Search for more papers by this author Originally published25 Jul 2022https://doi.org/10.1161/CIRCULATIONAHA.122.059661Circulation. 2022;146:276–278FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 278.Correspondence to: Ambarish Pandey, MD, MSCS, Assistant Professor of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047. Email ambarish.[email protected]edu

Editorial Commentary.

No AccessUrology PracticeSpecialty1 Sep 2022Editorial CommentaryThis article comments on the following:Gender and Racial Diversity among U.S. Urology Residency Programs and Efforts to Improve It: You Can’t Be What You Can’t See Jessica Dai Jessica DaiJessica Dai UT Southwestern Medical Center, Dallas, Texas More articles by this author View All Author Informationhttps://doi.org/10.1097/UPJ.0000000000000328.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Commentary." Urology Practice, 9(5), p. 473

Abstract SY31-04: Uncovering targetable dependencies of latent brain metastatic cells

Abstract Uncovering Targetable Dependencies of Latent Brain Metastatic Cells Srinivas Malladi, Department of Pathology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA ABSTRACT HER2+ breast cancer patients presenting with brain metastases have poor survival outcomes. Metachronous brain metastases or relapse are observed in approximately fifty percent of HER2+ breast cancer patients considered disease free after a variable length of time post primary diagnosis and treatment. Disseminated latent residual cells that survive current therapies are responsible for these relapses or metachronous metastasis. How disseminated tumor cells survive as latent/dormant entities for extended period before initiating metachronous metastasis is poorly understood. Moreover, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ is unknown and vital for better clinical management. Through a phenotypic screen in mice, we have isolated HER2+ latent (Lat) and brain metastatic (BM) cells.Transcriptomic and metabolic profiles of these brain-tropic breast cancer cells identified actionable dependencies and unique therapeutic opportunities. Brain-tropic Lat and metastatic cells have distinct metabolic profiles that determine their metastatic fitness. Both latent and metastatic cells survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Likewise, xCT expression was significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models. Lactate secreted by aggressive metastatic cells limits innate immune surveillance and triggers overt metastasis. Furthermore, transcriptomic analysis identified augmented AXL expression. Depleting or inhibiting AXL in these HER2 targeted therapy resistant brain-tropic cells attenuates metastatic incidence. In sum, by investigating phenotypically distinct brain-tropic latent and metastatic cells, we uncovered the impact of metabolic diversity and adaptations on metastatic fitness and identified targetable vulnerabilities. Citation Format: Srinivas Malladi. Uncovering targetable dependencies of latent brain metastatic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY31-04.

The impact of NSCLC disease evolution and treatment on pre- and post-diagnosis weight loss and cachexia designation.

e24098 Background: While cancer cachexia is associated with increased morbidity/mortality, little is known about longitudinal weight changes and opportunities for intervention pre- and post-diagnosis in this patient population. We therefore aimed to characterize body weight trajectories pre- and post- non-small cell lung cancer (NSCLC) diagnosis in patients without and with cachexia. Methods: Data were retrospectively extracted for each patient pre- and post-diagnosis of NSCLC from inpatient and outpatient visits within the UT Southwestern Medical Center Healthcare System. 3830 participants were screened with a NSCLC diagnosis between May 2005 to December 2019. Of these, 661 patients had a body weight recorded at cancer diagnosis and at least one body weight pre-diagnosis. The primary outcome was weight change over time. Other measures included defining associations between weight change and tumor pathology, stage of disease, and other clinical characteristics. Results: NSCLC patients without cachexia at cancer diagnosis were weight stable up to 12-months pre-diagnosis (+1.0±0.3% body weight; p = 0.01). Weight loss post-diagnosis was driven by stage of disease (stage 1/2: 0.4±0.5% body weight vs. stage 3/4: 4.8±0.9% body weight p = 0.0008) and treatment with chemotherapy (p &lt; 0.0001). NSCLC patients with cachexia at cancer diagnosis lost weight pre-diagnosis (8.8±0.5% body weight; p &lt; 0.0001), with 25% of this weight loss occurring between 6- and 12-months pre-diagnosis. Assessing weight change over 12 months opposed to 6 months resulted in a 32% increase in NSCLC patients with cachexia at cancer diagnosis (p = 0.006). By 12-months post-diagnosis, 62% of surviving late-stage and 45% of early-stage NSCLC patients had met the criteria for cachexia. Patients on average remained free of weight loss for 150±6.4 days or had pre-cachexia for 146±7.2 days prior to transitioning to a more advanced stage of the syndrome. Conclusions: Significant weight loss in NSCLC patients initiated as far back as 12 months prior to a cancer diagnosis as opposed to a shorter 6-month interval currently used to define patients with cachexia. Therefore, detection of earlier weight loss should be prioritized in high-risk NSCLC screening candidates. Finally, advanced NSCLC patients develop cachexia post-diagnosis irrespective of previous weight history, highlighting the impact of treatment iatrogenicity and/or refractory disease on cachexia development.