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Comparison of cardiac autonomic innervation in post-mortem tissue from individuals with kidney failure and preserved kidney function

Soomro, Qandeel; Mezzano, Valeria; Narula, Navneet; Rapkiewicz, Amy; Loomis, Cynthia; Charytan, David M
PMID: 38869950
ISSN: 1555-905x
CID: 5669312

Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides

Claudio Quiros, Adalberto; Coudray, Nicolas; Yeaton, Anna; Yang, Xinyu; Liu, Bojing; Le, Hortense; Chiriboga, Luis; Karimkhan, Afreen; Narula, Navneet; Moore, David A; Park, Christopher Y; Pass, Harvey; Moreira, Andre L; Le Quesne, John; Tsirigos, Aristotelis; Yuan, Ke
Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.
PMID: 38862472
ISSN: 2041-1723
CID: 5669022

Amyloid and collagen templates in aortic valve calcification

Jayaraman, Shobini; Narula, Navneet; Narula, Jagat; Gursky, Olga
Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium-calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid-calcium-collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification.
PMID: 38845326
ISSN: 1471-499x
CID: 5665802

Integrative multi-omics profiling in human decedents receiving pig heart xenografts

Schmauch, Eloi; Piening, Brian; Mohebnasab, Maedeh; Xia, Bo; Zhu, Chenchen; Stern, Jeffrey; Zhang, Weimin; Dowdell, Alexa K; Kim, Jacqueline I; Andrijevic, David; Khalil, Karen; Jaffe, Ian S; Loza, Bao-Li; Gragert, Loren; Camellato, Brendan R; Oliveira, Michelli F; O'Brien, Darragh P; Chen, Han M; Weldon, Elaina; Gao, Hui; Gandla, Divya; Chang, Andrew; Bhatt, Riyana; Gao, Sarah; Lin, Xiangping; Reddy, Kriyana P; Kagermazova, Larisa; Habara, Alawi H; Widawsky, Sophie; Liang, Feng-Xia; Sall, Joseph; Loupy, Alexandre; Heguy, Adriana; Taylor, Sarah E B; Zhu, Yinan; Michael, Basil; Jiang, Lihua; Jian, Ruiqi; Chong, Anita S; Fairchild, Robert L; Linna-Kuosmanen, Suvi; Kaikkonen, Minna U; Tatapudi, Vasishta; Lorber, Marc; Ayares, David; Mangiola, Massimo; Narula, Navneet; Moazami, Nader; Pass, Harvey; Herati, Ramin S; Griesemer, Adam; Kellis, Manolis; Snyder, Michael P; Montgomery, Robert A; Boeke, Jef D; Keating, Brendan J
In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.
PMID: 38760586
ISSN: 1546-170x
CID: 5654102

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.
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.
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