Pulmonology Commons^™

Hsp90 Inhibitor, At13387 Mitigates Chronic Lung Injury In Pre-Pubertal Mice: A Therapeutic Axis In Bronchopulmonary Dysplasia, Pavel A. Solopov, Christiana Dimitropoulou, John D. Catravas, Ruben M. L. Colunga Biancatelli

Bioelectrics Publications

Exposure to hydrochloric acid (HCl) can provoke severe chronic pulmonary injury. Children are particularly vulnerable due to their smaller airways, higher respiratory rate, and stronger inflammatory response; yet no countermeasures exist for HCl-induced chronic lung injury in the pediatric population. We have previously demonstrated the involvement of HSP90 during HCl-induced lung injury in pre-pubertal (p24) mice, who develop stronger persistent inflammation with higher NLRP3 inflammasome activation, but less pulmonary fibrosis compared to adults. Here, we tested the hypothesis that post-treatment with the second-generation HSP90 inhibitor AT13387 (Onalespib), administered subcutaneously beginning 24 h after HCl instillation, would prevent HCl-induced chronic lung …

Role Of Cellular Stress Responses In Innate Immune Defense Against Acute Respiratory Infections, Amit Sharma

LSU Doctoral Dissertations

The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is an important regulator of innate immune cells. However, its role in pulmonary innate host defenses remains poorly understood. This dissertation elucidates the dual, context-dependent role of IRE1α in host defense against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. We demonstrate IRE1α’s function as both a detrimental mediator of acute pathology and an essential facilitator of innate immune memory. Our work revealed that acute IRE1α activation during primary MRSA infection is detrimental. In lungs and alveolar macrophages (AMs), IRE1α is activated in response to MRSA infection. Consequently, IRE1α activation triggers a hyperinflammatory …

Prognostic Significance Of Micropapillary Pattern And Risk Factors In Patients With Resected Stage I Lung Adenocarcinoma And Possible Benefit Of Adjuvant Therapy: A Real-World Multicenter Study, Jianjie Li, Yujia Chi, Bo Jia, Qiwen Zheng, Minghan Yuan, Jianjun Zhang, Aishen Zhou, Wei Sun, Yue Yang, Jun Zhao, Tongtong An, Yuyan Wang, Minglei Zhuo, Xue Yang, Hanxiao Chen, Jingjing Wang, Xiaoyu Zhai, Yidi Tai, Yuling He, Lingdong Kong, Xumeng Ji, Yiliang Liu, Nan Wu, Ken Onodera, Paul Van Schil, Mathew Thomas, Fan Yang, Ziping Wang

Faculty, Staff and Student Publications

Background: Micropapillary (MP) pattern has been identified as a negative prognostic factor in patients with lung adenocarcinoma, but it has not been recognized as a high-risk factor for patients with stage IB lung adenocarcinoma treated with adjuvant chemotherapy. This multicenter cohort study aimed to evaluate the prognostic value of histological subtypes for stage I lung adenocarcinoma and to determine the relative survival benefit of adjuvant chemotherapy for subgroups based on MP pattern.

Methods: This retrospective study included 412 patients with stage I lung adenocarcinoma [according the eighth edition of the tumor-node-metastasis (TNM) classification] with MP pattern who underwent complete surgical …

Identification And Preclinical Assessment Of Novel Therapeutic Modalities In Environmental Exposure-Induced Lung Disease, Aaron D. Schwab

Theses & Dissertations

Environmental lung diseases are preventable respiratory conditions either caused or made worse by inhaled environmental exposures. Contemporarily, environmental lung diseases are most associated with workplace exposures given specific occupational processes aerosolize inflammatory agents that can be inhaled at high concentrations. Although a considerable amount is known regarding immunoglobulin (Ig)E-mediated responses to environmental exposures, little is known about non-IgE mediated respiratory conditions resulting from lipopolysaccharide (LPS)-enriched organic dust exposure(s). Chronic respiratory diseases such as asthma, hypersensitivity pneumonitis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis have all been identified as environmental lung diseases caused or exacerbated by such environmental dusts. Therapeutic …

Pulmonopoly: A Game-Based Approach To Teach And Reinforce Basic Concepts Of Pulmonary Medicine To Medical Students, Michael Dong, James Uricheck, Urvashi Vaid

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

INTRODUCTION: Pulmonopoly is an innovative active-learning medical board game addressses core pulmonary concepts in an engaging, competitive style. The strength of Pulmonopoly lies in its ability to combine ease of setup and play with comprehensive content coverage that comprises a significant proportion of national board examinations, offering a gamification experience that can be readily applied in different settings and modified for learner levels.

METHODS: We created an instructional game, Pulmonopoly, based on pulmonary content delivered to preclinical medical students and required for national board examinations. We invited first-year medical students to participate in 60-minute small-group sessions. Content addressed pulmonary subject …

Leveraging Clinical Standards To Improve The Translational Relevance Of Therapies For Experimental Spinal Cord Injury, Aaron L. Silverstein

Theses and Dissertations--Neuroscience

Efforts to improve treatment of spinal cord injury (SCI) often use animals to develop effective therapeutics, intending to improve the survival and the quality of life of persons with SCI. Over half of all SCIs in the United States occur at the cervical level and often cause locomotor deficits and life-threatening breathing dysfunction. Thus, my dissertation is focused on this important patient population.

After beginning with a description of translational research and surveying SCI from a clinical standpoint, I turned to describe experimental models of cervical SCI and more detailed neuroimmunological findings relevant to my work. Then, I conducted a …

Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury In Mice, Gregory Nicholson, Nicholas Richards, Janette Lockett, My Boi Ly, Raj V. Nair, Woong-Ki Kim, K. Yaragudri Vinod, Nagaraja Nagre

Department of Biomedical and Translational Sciences Faculty Publications

Background: Exposure to sulfur mustard (SM; 2,2′-dichlorodiethyl sulfide) causes toxicity in the human body, particularly the lungs. The molecular mechanisms of SM-induced lung damage are elusive, and no effective treatments exist. This study explores the anti-inflammatory potential of cannabinoid receptor 2 (CB2R) activation in mitigating acute lung injury (ALI) and inflammation induced by 2-chloroethyl ethyl sulfide (CEES), a structural analog of SM. Methods: C57BL/6J mice were exposed to CEES via intratracheal administration to model ALI. CB2R activation was achieved through the intraperitoneal administration of HU308, a selective synthetic agonist. ALI and inflammation were evaluated at 48 h post-exposure to CEES. …

Delta-Like Ligand 3 (Dll3) Landscape In Pulmonary And Extra-Pulmonary Neuroendocrine Neoplasms, Alejandra G Serrano, Pedro Rocha, Cibelle Freitas Lima, Allison Stewart, Bingnan Zhang, Lixia Diao, Junya Fujimoto, Robert J Cardnell, Wei Lu, Khaja Khan, Beate Sable, Aaron R Ellison, Ignacio I Wistuba, Kyle F Concannon, Daniel M Halperin, Czerniak Bogdan, Kanishka Sircar, Miao Zhang, Kasey Cargill, Qi Wang, Ana Aparicio, Alexander Lazar, Sharia Hernandez, Jeannelyn Estrella, Preetha Ramalingam, Adel El-Naggar, Neda Kalhor, Carl M Gay, Lauren Averett Byers, Luisa M Solis Soto

Faculty, Staff and Student Publications

Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression …

Multiregional Transcriptomic Profiling Provides Improved Prognostic Insight In Localized Non-Small Cell Lung Cancer, Chenyang Li, Thinh T Nguyen, Jian-Rong Li, Xingzhi Song, Junya Fujimoto, Latasha Little, Curtis Gumb, Chi-Wan B Chow, Ignacio I Wistuba, Andrew P Futreal, Jianhua Zhang, Shawna M Hubert, John V Heymach, Jia Wu, Christopher I Amos, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

Molecular Landscape Of Erbb2 Alterations In 3000 Advanced Nsclc Patients, Lingzhi Hong, Sonia Patel, Leylah M Drusbosky, Yuanyuan Xiong, Rongrong Chen, Ruixuan Geng, Simon Heeke, Monique Nilsson, Jia Wu, John V Heymach, Yingyi Wang, Jianjun Zhang, Xiuning Le

Faculty, Staff and Student Publications

ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 …

Premalignant Progression In The Lung: Knowledge Gaps And Novel Opportunities For Interception Of Non-Small Cell Lung Cancer An Official American Thoracic Society Research Statement, Seyed Javad Moghaddam, Rajkumar Savai, Ramin Salehi-Rad, Shreoshi Sengupta, Michael N Kammer, Pierre Massion, Jennifer E Beane, Edwin J Ostrin, Carmen Priolo, Meredith A Tennis, Laura P Stabile, Alison K Bauer, Catherine R Sears, Eva Szabo, M Patricia Rivera, Charles A Powell, Humam Kadara, Brendan J Jenkins, Steven M Dubinett, A Mcgarry Houghton, Carla F Kim, Robert L Keith

Faculty, Staff and Student Publications

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the …

Overcoming Egfr-Tki Resistance By Targeting The Tumor Microenvironment, Jinsong Zhang, Natalie Vokes, Man Li, Jiachen Xu, Hua Bai, Jie Wang, Zhijie Wang, Jianjun Zhang

Faculty, Staff and Student Publications

Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer (NSCLC). Currently, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations. Nevertheless, most patients inevitably confront the challenge of drug resistance. This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings. This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms, with a specific emphasis on unraveling the …

Inhibition Of Ulk1/2 And Kras G12c Controls Tumor Growth In Preclinical Models Of Lung Cancer, Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin Mcmahon

Faculty, Staff and Student Publications

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer …

Lung Cell Transplantation For Pulmonary Fibrosis, Irit Milman Krentsis, Yangxi Zheng, Chava Rosen, Sarah Y Shin, Christa Blagdon, Einav Shoshan, Yuan Qi, Jing Wang, Sandeep K Yadav, Esther Bachar Lustig, Elias Shetzen, Burton F Dickey, Harry Karmouty-Quintana, Yair Reisner

Faculty, Staff and Student Publications

Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors …

Translational Modeling-Based Evidence For Enhanced Efficacy Of Standard-Of-Care Drugs In Combination With Anti-Microrna-155 In Non-Small-Cell Lung Cancer, Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D Butner, Carmine Schiavone, Dan G Duda, Ahmed O Kaseb, Caroline Chung, Eugene J Koay, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg …

Vesicle-Associated Membrane Proteins In Airway Mucin Secretion, Boxuan Yang

Dissertations and Theses (Open Access)

Mucus plays a vital role in shielding the lungs against harmful substances such as particles, pathogens, and chemicals inhaled from the environment. It captures these harmful elements, and ciliary action helps to expel them from the lungs. Paradoxically, malfunctioning of mucus induces the development of various respiratory illnesses, including asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. Despite extensive research on controlling mucin production and hydration, the process of secretion is not yet fully comprehended.

Mucin undergoes regulated secretion at two rates: a low baseline rate and a high stimulated rate. Over the past 25 years, …

A Comparison Of Tracheal Intubation Using Direct Laryngoscope And Video Laryngoscope In The Sellick And Trendelenburg Position With That Using Direct Laryngoscope In The Supine Sniffing Position: A Randomized Controlled Trial, Yun-Jeong Chae, Jung-Yoon Moon, Min-Gyu Lee, Han-Bum Joe

Faculty, Staff and Student Publications

Background: Tracheal intubation in the Sellick and Trendelenburg position (ST position) can prevent pulmonary aspiration but increase the difficulty of tracheal intubation. We compared tracheal intubation using video and direct laryngoscopy in the ST position with direct laryngoscopy in the supine sniffing position to evaluate the overall intubation performance. Methods: One hundred and twenty patients were randomly assigned to three groups: direct laryngoscope in the supine sniffing position (control), direct laryngoscope in the ST position (ST direct), and video laryngoscope in the ST position (ST video). The primary outcome was the intubation time; secondary outcomes included the first …

Epigenome-Wide Association Study Of Lung Cancer Among Never Smokers In Two Prospective Cohorts In Shanghai, China, Mohammad L Rahman, Charles E Breeze, Xiao-Ou Shu, Jason Y Y Wong, Batel Blechter, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas A Bell, Wei Zheng, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted.

METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse …

The Calcineurin-Nfatc Pathway Modulates The Lipid Mediators In Bal Fluid Extracellular Vesicles, Thereby Regulating Microvascular Endothelial Cell Barrier Function, Manjula Karpurapu, Yunjuan Nie, Sangwoon Chung, Jiasheng Yan, Patrick Dougherty, Sonal Pannu, Jon Wisler, Ryan Harkless, Narasimham Parinandi, Evgeny Berdyshev, Dehua Pei, John W Christman

Faculty, Staff and Student Publications

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse …

Age At Lung Cancer Diagnosis In Females Versus Males Who Never Smoke By Race And Ethnicity, Batel Blechter, Jason Y Y Wong, Li-Hsin Chien, Kouya Shiraishi, Xiao-Ou Shu, Qiuyin Cai, Wei Zheng, Bu-Tian Ji, Wei Hu, Mohammad L Rahman, Hsin-Fang Jiang, Fang-Yu Tsai, Wen-Yi Huang, Yu-Tang Gao, Xijing Han, Mark D Steinwandel, Gong Yang, Yihe G Daida, Su-Ying Liang, Scarlett L Gomez, Mindy C Derouen, W Ryan Diver, Ananya G Reddy, Alpa V Patel, Loïc Le Marchand, Christopher Haiman, Takashi Kohno, Iona Cheng, I-Shou Chang, Chao Agnes Hsiung, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke.

METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes.

RESULTS: We found that among Chinese individuals diagnosed with lung cancer …

Advancing Primary Ciliary Dyskinesia Diagnosis Through High-Speed Video Microscopy Analysis, Wilfredo De Jesús-Rojas, Zachary J Demetriou, José Muñiz-Hernández, Gabriel Rosario-Ortiz, Frances M Quiñones, Marcos J Ramos-Benitez, Ricardo A Mosquera

Faculty, Staff and Student Publications

Primary ciliary dyskinesia (PCD) is an inherited disorder that impairs motile cilia, essential for respiratory health, with a reported prevalence of 1 in 16,309 within Hispanic populations. Despite 70% of Puerto Rican patients having the RSPH4A [c.921+3_921+6del (intronic)] founder mutation, the characterization of the ciliary dysfunction remains unidentified due to the unavailability of advanced diagnostic modalities like High-Speed Video Microscopy Analysis (HSVA). Our study implemented HSVA for the first time on the island as a tool to better diagnose and characterize the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in Puerto Rican patients. By applying HSVA, we analyzed the ciliary beat frequency …

Omics-Based Profiles And Biomarkers Of Respiratory Infections: Are We There Yet?, Jezreel Pantaleon Garcia, Scott E Evans

Faculty, Staff and Student Publications

Descriptive omics-based clinical research provides valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies https://bit.ly/4bjJsvL

An Atlas Of Epithelial Cell States And Plasticity In Lung Adenocarcinoma, Guangchun Han, Ansam Sinjab, Zahraa Rahal, Anne M Lynch, Warapen Treekitkarnmongkol, Yuejiang Liu, Alejandra G Serrano, Jiping Feng, Ke Liang, Khaja Khan, Wei Lu, Sharia D Hernandez, Yunhe Liu, Xuanye Cao, Enyu Dai, Guangsheng Pei, Jian Hu, Camille Abaya, Lorena I Gomez-Bolanos, Fuduan Peng, Minyue Chen, Edwin R Parra, Tina Cascone, Boris Sepesi, Seyed Javad Moghaddam, Paul Scheet, Marcelo V Negrao, John V Heymach, Mingyao Li, Steven M Dubinett, Christopher S Stevenson, Avrum E Spira, Junya Fujimoto, Luisa M Solis, Ignacio I Wistuba, Jichao Chen, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver …

Biomarker-Directed Targeted Therapy Plus Durvalumab In Advanced Non-Small-Cell Lung Cancer: A Phase 2 Umbrella Trial, Benjamin Besse, Elvire Pons-Tostivint, Keunchil Park, Sylvia Hartl, Patrick M Forde, Maximilian J Hochmair, Mark M Awad, Michael Thomas, Glenwood Goss, Paul Wheatley-Price, Frances A Shepherd, Marie Florescu, Parneet Cheema, Quincy S C Chu, Sang-We Kim, Daniel Morgensztern, Melissa L Johnson, Sophie Cousin, Dong-Wan Kim, Mor T Moskovitz, David Vicente, Boaz Aronson, Rosalind Hobson, Helen J Ambrose, Sajan Khosla, Avinash Reddy, Deanna L Russell, Mohamed Reda Keddar, James P Conway, J Carl Barrett, Emma Dean, Rakesh Kumar, Marlene Dressman, Philip J Jewsbury, Sonia Iyer, Simon T Barry, Jan Cosaert, John V Heymach

Faculty, Staff and Student Publications

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance—which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment—and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure …

Development And Validation Of A Nomogram For Predicting Pulmonary Infection In Patients Receiving Immunosuppressive Drugs, Chuxuan Luo, Yue Zhang, Jiajie Zhang, Chen Jin, Xiaolan Ye, Yan Ren, Huajuan Shen, Maosheng Chen, Yiwen Li, Qiang He, Guangbiao Xu, Lina Shao

Faculty, Staff and Student Publications

Objective: Pulmonary infection (PI), a severe complication of immunosuppressive therapy, affects patients' prognosis. As part of this study, we aimed to construct a pulmonary infection prediction (PIP) model and validate it in patients receiving immunosuppressive drugs (ISDs). Methods: Totally, 7,977 patients being treated with ISDs were randomised 7:3 to the developing (n = 5,583) versus validation datasets (n = 2,394). Our predictive nomogram was established using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. With the use of the concordance index (C-index) and calibration curve, the prediction performance of the final model was …

Kvx-053, A Protein Tyrosine Phosphatase 4a3 Inhibitor, Ameliorates Sars-Cov-2 Spike Protein Subunit 1 - Induced Acute Lung Injury In Mice, Pavel A. Solopov, Ruben Manuel Luciano Colunga Biancatelli, Tierney Day, Betsy Gregory, Elizabeth R. Sharlow, John S. Lazo, John D. Catravas

Bioelectrics Publications

The Acute Respiratory Distress Syndrome (ARDS), often preceded by acute lung injury (ALI), is characterized by the accumulation of inflammatory fluid in the lung alveoli, leaky alveolar epithelium and endothelium, and overexpression of pro-inflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in COVID-19 patients. The Spike protein of SARS-CoV-2 binds to lung ACE2 and, in addition to facilitating viral cell entry, it plays an important role in the development of ALI and ARDS, especially in the later phases of COVID-19 as well as long COVID. Protein tyrosine phosphatase (PTP) 4A3 is …

Prioritizing Clinically Significant Lung Cancer Somatic Mutations For Targeted Therapy Through Efficient Ngs Data Filtering System, Jinlian Wang, Hui Li, Hongfang Liu

Faculty, Staff and Student Publications

In the realm of lung cancer treatment, where genetic heterogeneity presents formidable challenges, precision oncology demands an exacting approach to identify and hierarchically sort clinically significant somatic mutations. Current Next-Generation Sequencing (NGS) data filtering pipelines, while utilizing various external databases for mutation screening, often fall short in comprehensive integration and flexibility needed to keep pace with the evolving landscape of clinical data. Our study introduces a sophisticated NGS data filtering system, which not only aggregates but effectively synergizes diverse data sources, encompassing genetic variants, gene functions, clinical evidence, and an extensive body of literature. This system is distinguished by a …

Risk Factors, Incidence, And Outcomes Associated With Clinically Significant Airway Ischemia, Gloria Li, Zejian Liu, Marcelo Salan-Gomez, Emma Keeney, Ethan D'Silva, Babith Mankidy, Andres Leon, Aladdein Mattar, Abdusallam Elsennousi, Jennalee Coster, Anupam Kumar, Bruno Rodrigues, Meng Li, Alexis Shafii, Puneet Garcha, Gabriel Loor

Faculty, Staff and Students Publications

Airway complications following lung transplantation remain an important cause of morbidity and mortality. We aimed to identify the incidence, risk factors and outcomes associated with clinically significant airway ischemia (CSAI) in our center. We reviewed 217 lung transplants (386 airway anastomoses) performed at our institution between February 2016 and December 2020. Airway images were graded using the 2018 ISHLT grading guidelines modified slightly for retrospective analysis. Airways were considered to have CSAI if they developed ischemia severity >B2, stenosis >50%, and/or any degree of dehiscence within 6-months of transplant. Regression analyses were used to evaluate outcomes and risk factors for …

Allergic Bronchopulmonary Aspergillosis: Radiological And Microbiological Profile Of Patients Presented In An Outpatient Pulmonary Clinic In A Developing Country, Nousheen Iqbal, Muhammad Irfan, Mustafa Bin Ali Zubairi, Maaha Ayub, Safia Awan, Kauser Jabeen, Ali Bin Sarwar Zubairi

Section of Pulmonary & Critical Care

There is limited data available about allergic bronchopulmonary aspergillosis (ABPA) in Pakistan. The aim of the study was to describe the radiological and microbiological profile of ABPA patients presenting to the outpatient pulmonary clinic of a tertiary care hospital in Karachi, Pakistan. A retrospective study was conducted on ABPA patients who presented to the pulmonary outpatient clinic at Aga Khan University Hospital, Karachi, Pakistan, from January 2017 to December 2019. Data was collected on microbiology and radiology features on predesigned proforma. A total of 7759 asthmatic patients presented at the outpatient pulmonology clinic during the study period. Of the 245 …