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Updates on lung adenocarcinoma: invasive size, grading and STAS

Willner, Jonathan; Narula, Navneet; Moreira, Andre L
Advancements in the classification of lung adenocarcinoma have resulted in significant changes in pathological reporting. The eighth edition of the tumour-node-metastasis (TNM) staging guidelines calls for the use of invasive size in staging in place of total tumour size. This shift improves prognostic stratification and requires a more nuanced approach to tumour measurements in challenging situations. Similarly, the adoption of new grading criteria based on the predominant and highest-grade pattern proposed by the International Association for the Study of Lung Cancer (IASLC) shows improved prognostication, and therefore clinical utility, relative to previous grading systems. Spread through airspaces (STAS) is a form of tumour invasion involving tumour cells spreading through the airspaces, which has been highly researched in recent years. This review discusses updates in pathological T staging, adenocarcinoma grading and STAS and illustrates the utility and limitations of current concepts in lung adenocarcinoma.
PMID: 37872108
ISSN: 1365-2559
CID: 5612982

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Dolgalev, Igor; Zhou, Hua; Murrell, Nina; Le, Hortense; Sakellaropoulos, Theodore; Coudray, Nicolas; Zhu, Kelsey; Vasudevaraja, Varshini; Yeaton, Anna; Goparaju, Chandra; Li, Yonghua; Sulaiman, Imran; Tsay, Jun-Chieh J; Meyn, Peter; Mohamed, Hussein; Sydney, Iris; Shiomi, Tomoe; Ramaswami, Sitharam; Narula, Navneet; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Cheng, Wei-Yi; Cai, James; Punekar, Salman; Velcheti, Vamsidhar; Sterman, Daniel H; Poirier, J T; Neel, Ben; Wong, Kwok-Kin; Chiriboga, Luis; Heguy, Adriana; Papagiannakopoulos, Thales; Nadorp, Bettina; Snuderl, Matija; Segal, Leopoldo N; Moreira, Andre L; Pass, Harvey I; Tsirigos, Aristotelis
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
PMCID:10632519
PMID: 37938580
ISSN: 2041-1723
CID: 5609852

DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress

Yepuri, Gautham; Ramirez, Lisa M; Theophall, Gregory G; Reverdatto, Sergei V; Quadri, Nosirudeen; Hasan, Syed Nurul; Bu, Lei; Thiagarajan, Devi; Wilson, Robin; Díez, Raquel López; Gugger, Paul F; Mangar, Kaamashri; Narula, Navneet; Katz, Stuart D; Zhou, Boyan; Li, Huilin; Stotland, Aleksandr B; Gottlieb, Roberta A; Schmidt, Ann Marie; Shekhtman, Alexander; Ramasamy, Ravichandran
Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
PMCID:10616211
PMID: 37903764
ISSN: 2041-1723
CID: 5610492

Nonischemic Cardiomyopathy With Myocardial Calcinosis Masquerading as Cardiac Amyloidosis

Singh, Arushi; Kadosh, Bernard S; Grossman, Kelsey; Donnino, Robert; Narula, Navneet; Zhou, Fang; DiVita, Michael; Smith, Deane E; Moazami, Nader; Chang, Stephanie H; Angel, Luis F; Reyentovich, Alex
PMID: 37492988
ISSN: 1941-3297
CID: 5620132

SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels

Eberhardt, Natalia; Noval, Maria Gabriela; Kaur, Ravneet; Amadori, Letizia; Gildea, Michael; Sajja, Swathy; Das, Dayasagar; Cilhoroz, Burak; Stewart, O'Jay; Fernandez, Dawn M; Shamailova, Roza; Guillen, Andrea Vasquez; Jangra, Sonia; Schotsaert, Michael; Newman, Jonathan D; Faries, Peter; Maldonado, Thomas; Rockman, Caron; Rapkiewicz, Amy; Stapleford, Kenneth A; Narula, Navneet; Moore, Kathryn J; Giannarelli, Chiara
Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.
PMID: 38076343
ISSN: 2731-0590
CID: 5589542

Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study

Loupy, Alexandre; Goutaudier, Valentin; Giarraputo, Alessia; Mezine, Fariza; Morgand, Erwan; Robin, Blaise; Khalil, Karen; Mehta, Sapna; Keating, Brendan; Dandro, Amy; Certain, Anaïs; Tharaux, Pierre-Louis; Narula, Navneet; Tissier, Renaud; Giraud, Sébastien; Hauet, Thierry; Pass, Harvey I; Sannier, Aurélie; Wu, Ming; Griesemer, Adam; Ayares, David; Tatapudi, Vasishta; Stern, Jeffrey; Lefaucheur, Carmen; Bruneval, Patrick; Mangiola, Massimo; Montgomery, Robert A
BACKGROUND:Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach. METHODS:We did a complete phenotyping of two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling and cell deconvolution. Xenografts before implantation, wild-type pig kidney autografts, as well as wild-type, non-transplanted pig kidneys with and without ischaemia-reperfusion were used as controls. FINDINGS:cells. Both xenografts showed increased expression of genes biologically related to a humoral response, including monocyte and macrophage activation, natural killer cell burden, endothelial activation, complement activation, and T-cell development. Whole-transcriptome digital spatial profiling showed that antibody-mediated injury was mainly located in the glomeruli of the xenografts, with significant enrichment of transcripts associated with monocytes, macrophages, neutrophils, and natural killer cells. This phenotype was not observed in control pig kidney autografts or in ischaemia-reperfusion models. INTERPRETATION:Despite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results. FUNDING:OrganX and MSD Avenir.
PMID: 37598688
ISSN: 1474-547x
CID: 5598182

MAVS signaling is required for preventing persistent chikungunya heart infection and chronic vascular tissue inflammation

Noval, Maria G; Spector, Sophie N; Bartnicki, Eric; Izzo, Franco; Narula, Navneet; Yeung, Stephen T; Damani-Yokota, Payal; Dewan, M Zahidunnabi; Mezzano, Valeria; Rodriguez-Rodriguez, Bruno A; Loomis, Cynthia; Khanna, Kamal M; Stapleford, Kenneth A
Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in major innate immunity signaling components, we found that signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS signaling, persistent infection leads to focal myocarditis and vasculitis of the large vessels attached to the base of the heart. Large vessel vasculitis was observed for up to 60 days post infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.
PMCID:10400619
PMID: 37537212
ISSN: 2041-1723
CID: 5594762

Pig-to-human heart xenotransplantation in two recently deceased human recipients

Moazami, Nader; Stern, Jeffrey M; Khalil, Karen; Kim, Jacqueline I; Narula, Navneet; Mangiola, Massimo; Weldon, Elaina P; Kagermazova, Larisa; James, Les; Lawson, Nikki; Piper, Greta L; Sommer, Philip M; Reyentovich, Alex; Bamira, Daniel; Saraon, Tajinderpal; Kadosh, Bernard S; DiVita, Michael; Goldberg, Randal I; Hussain, Syed T; Chan, Justin; Ngai, Jennie; Jan, Thomas; Ali, Nicole M; Tatapudi, Vasishta S; Segev, Dorry L; Bisen, Shivani; Jaffe, Ian S; Piegari, Benjamin; Kowalski, Haley; Kokkinaki, Maria; Monahan, Jeffrey; Sorrells, Lori; Burdorf, Lars; Boeke, Jef D; Pass, Harvey; Goparaju, Chandra; Keating, Brendan; Ayares, David; Lorber, Marc; Griesemer, Adam; Mehta, Sapna A; Smith, Deane E; Montgomery, Robert A
Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.
PMID: 37488288
ISSN: 1546-170x
CID: 5595152

HHV-6 Myocarditis Progressing to Ventricular Standstill Requiring Cardiac Transplant

Golob, S; Nazeer, H; Kadosh, B; Goldberg, R; Narula, N; Moazami, N; Rao, S; Reyentovich, A
Human herpesvirus-6 (HHV-6) is an increasingly recognized cause of myocarditis. We present the case of a 46-year-old woman who presented with fulminant HHV-6 myocarditis requiring heart transplantation. (Level of Difficulty: Advanced.)
Copyright
EMBASE:2024725238
ISSN: 2666-0849
CID: 5514222

The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis

Sud, Karan; Narula, Navneet; Aikawa, Elena; Arbustini, Eloisa; Pibarot, Philippe; Merlini, Giampaolo; Rosenson, Robert S; Seshan, Surya V; Argulian, Edgar; Ahmadi, Amir; Zhou, Fang; Moreira, Andre L; Côté, Nancy; Tsimikas, Sotirios; Fuster, Valentin; Gandy, Sam; Bonow, Robert O; Gursky, Olga; Narula, Jagat
Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.
PMID: 36624274
ISSN: 1759-5010
CID: 5410352