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Longitudinal Lower Airway Microbial Signatures of Acute Cellular Rejection in Lung Transplantation

Natalini, Jake G; Wong, Kendrew K; Nelson, Nathaniel C; Wu, Benjamin G; Rudym, Darya; Lesko, Melissa B; Qayum, Seema; Lewis, Tyler C; Wong, Adrian; Chang, Stephanie H; Chan, Justin C Y; Geraci, Travis C; Li, Yonghua; Wang, Chan; Li, Huilin; Pamar, Prerna; Schnier, Joseph; Mahoney, Ian J; Malik, Tahir; Darawshy, Fares; Sulaiman, Imran; Kugler, Matthias C; Singh, Rajbir; Collazo, Destiny E; Chang, Miao; Patel, Shrey; Kyeremateng, Yaa; McCormick, Colin; Barnett, Clea R; Tsay, Jun-Chieh J; Brosnahan, Shari B; Singh, Shivani; Pass, Harvey I; Angel, Luis F; Segal, Leopoldo N
PMID: 38358857
ISSN: 1535-4970
CID: 5633542

Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease

Sulaiman, Imran; Wu, Benjamin G; Chung, Matthew; Isaacs, Bradley; Tsay, Jun-Chieh J; Holub, Meredith; Barnett, Clea R; Kwok, Benjamin; Kugler, Matthias C; Natalini, Jake G; Singh, Shivani; Li, Yonghua; Schluger, Rosemary; Carpenito, Joseph; Collazo, Destiny; Perez, Luisanny; Kyeremateng, Yaa; Chang, Miao; Campbell, Christina D; Hansbro, Philip M; Oppenheimer, Beno W; Berger, Kenneth I; Goldring, Roberta M; Koralov, Sergei B; Weiden, Michael D; Xiao, Rui; D'Armiento, Jeanine; Clemente, Jose C; Ghedin, Elodie; Segal, Leopoldo N
PMID: 37677136
ISSN: 1535-4970
CID: 5606572

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

Pleural fluid microbiota as a biomarker for malignancy and prognosis

Kwok, Benjamin; Wu, Benjamin G; Kocak, Ibrahim F; Sulaiman, Imran; Schluger, Rosemary; Li, Yonghua; Anwer, Raheel; Goparaju, Chandra; Ryan, Daniel J; Sagatelian, Marla; Dreier, Matthew S; Murthy, Vivek; Rafeq, Samaan; Michaud, Gaetane C; Sterman, Daniel H; Bessich, Jamie L; Pass, Harvey I; Segal, Leopoldo N; Tsay, Jun-Chieh J
Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.
PMCID:9908925
PMID: 36755121
ISSN: 2045-2322
CID: 5426932

The lung microbiome, peripheral gene expression, and recurrence-free survival after resection of stage II non-small cell lung cancer

Peters, Brandilyn A; Pass, Harvey I; Burk, Robert D; Xue, Xiaonan; Goparaju, Chandra; Sollecito, Christopher C; Grassi, Evan; Segal, Leopoldo N; Tsay, Jun-Chieh J; Hayes, Richard B; Ahn, Jiyoung
BACKGROUND:Cancer recurrence after tumor resection in early-stage non-small cell lung cancer (NSCLC) is common, yet difficult to predict. The lung microbiota and systemic immunity may be important modulators of risk for lung cancer recurrence, yet biomarkers from the lung microbiome and peripheral immune environment are understudied. Such markers may hold promise for prediction as well as improved etiologic understanding of lung cancer recurrence. METHODS:In tumor and distant normal lung samples from 46 stage II NSCLC patients with curative resection (39 tumor samples, 41 normal lung samples), we conducted 16S rRNA gene sequencing. We also measured peripheral blood immune gene expression with nanoString®. We examined associations of lung microbiota and peripheral gene expression with recurrence-free survival (RFS) and disease-free survival (DFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression, and examined predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. RESULTS:Over a median of 4.8 years of follow-up (range 0.2-12.2 years), 43% of patients experienced a recurrence, and 50% died. In normal lung tissue, a higher abundance of classes Bacteroidia and Clostridia, and orders Bacteroidales and Clostridiales, were associated with worse RFS, while a higher abundance of classes Alphaproteobacteria and Betaproteobacteria, and orders Burkholderiales and Neisseriales, were associated with better RFS. In tumor tissue, a higher abundance of orders Actinomycetales and Pseudomonadales were associated with worse DFS. Among these taxa, normal lung Clostridiales and Bacteroidales were also related to worse survival in a previous small pilot study and an additional independent validation cohort. In peripheral blood, higher expression of genes TAP1, TAPBP, CSF2RB, and IFITM2 were associated with better DFS. Analysis of ROC curves revealed that lung microbiome and peripheral gene expression biomarkers provided significant additional recurrence risk discrimination over standard demographic and clinical covariates, with microbiome biomarkers contributing more to short-term (1-year) prediction and gene biomarkers contributing to longer-term (2-5-year) prediction. CONCLUSIONS:We identified compelling biomarkers in under-explored data types, the lung microbiome, and peripheral blood gene expression, which may improve risk prediction of recurrence in early-stage NSCLC patients. These findings will require validation in a larger cohort.
PMCID:9609265
PMID: 36303210
ISSN: 1756-994x
CID: 5358192

Controversies and challenges in lung cancer screening

Rampariag, Ravindra; Chernyavskiy, Igor; Al-Ajam, Mohammad; Tsay, Jun-Chieh J
Two large randomized controlled trials have shown mortality benefit from lung cancer screening (LCS) in high-risk groups. Updated guidelines by the United State Preventative Service Task Force in 2020 will allow for inclusion of more patients who are at high risk of developing lung cancer and benefit from screening. As medical clinics and lung cancer screening programs around the country continue to work on perfecting the LCS workflow, it is important to understand some controversial issues surrounding LCS that should be addressed. In this article, we identify some of these issues, including false positive rates of low-dose CT, over-diagnosis, cost expenditure, LCS disparities in minorities, and utility of biomarkers. We hope to provide clarity, potential solutions, and future directions on how to address these controversies.
PMID: 35907666
ISSN: 1532-8708
CID: 5277132

Chronic Lower Airway Dysbiosis with Human Oral Commensals Leads to Both Increased IL-17A and Immune Exhaustion Tone in the Lower Airways [Meeting Abstract]

Chang, M.; Kyeremateng, Y.; Collazo, D.; Kocak, I.; Singh, S.; Li, Y.; Tsay, J.; Segal, L. N.; Wu, B. G.
ISI:000792480401571
ISSN: 1073-449x
CID: 5238222

Microbial Signatures in Malignant Pleural Effusions [Meeting Abstract]

Kwok, B.; Wu, B. G.; Kocak, I. F.; Anwer, R.; Li, Y.; Goparaju, C.; Schluger, R.; Murthy, V.; Rafeq, S.; Bessich, J. L.; Tsay, J. J.; Pass, H. I.; Segal, L. N.
ISI:000792480400056
ISSN: 1073-449x
CID: 5266102

Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome

Sulaiman, Imran; Chung, Matthew; Angel, Luis; Tsay, Jun-Chieh J; Wu, Benjamin G; Yeung, Stephen T; Krolikowski, Kelsey; Li, Yonghua; Duerr, Ralf; Schluger, Rosemary; Thannickal, Sara A; Koide, Akiko; Rafeq, Samaan; Barnett, Clea; Postelnicu, Radu; Wang, Chang; Banakis, Stephanie; Pérez-Pérez, Lizzette; Shen, Guomiao; Jour, George; Meyn, Peter; Carpenito, Joseph; Liu, Xiuxiu; Ji, Kun; Collazo, Destiny; Labarbiera, Anthony; Amoroso, Nancy; Brosnahan, Shari; Mukherjee, Vikramjit; Kaufman, David; Bakker, Jan; Lubinsky, Anthony; Pradhan, Deepak; Sterman, Daniel H; Weiden, Michael; Heguy, Adriana; Evans, Laura; Uyeki, Timothy M; Clemente, Jose C; de Wit, Emmie; Schmidt, Ann Marie; Shopsin, Bo; Desvignes, Ludovic; Wang, Chan; Li, Huilin; Zhang, Bin; Forst, Christian V; Koide, Shohei; Stapleford, Kenneth A; Khanna, Kamal M; Ghedin, Elodie; Segal, Leopoldo N
Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.
PMID: 34465900
ISSN: 2058-5276
CID: 4998422

Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial

Nickols, Nicholas G; Goetz, Matthew B; Graber, Christopher J; Bhattacharya, Debika; Soo Hoo, Guy; Might, Matthew; Goldstein, David B; Wang, Xinchen; Ramoni, Rachel; Myrie, Kenute; Tran, Samantha; Ghayouri, Leila; Tsai, Sonny; Geelhoed, Michelle; Makarov, Danil; Becker, Daniel J; Tsay, Jun-Chieh; Diamond, Melissa; George, Asha; Al-Ajam, Mohammad; Belligund, Pooja; Montgomery, R Bruce; Mostaghel, Elahe A; Sulpizio, Carlie; Mi, Zhibao; Dematt, Ellen; Tadalan, Joseph; Norman, Leslie E; Briones, Daniel; Clise, Christina E; Taylor, Zachary W; Huminik, Jeffrey R; Biswas, Kousick; Rettig, Matthew B
BACKGROUND:Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. METHODS:This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3-5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. DISCUSSION/CONCLUSIONS:In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT04397718. Registered on May 21, 2020.
PMCID:8256647
PMID: 34225789
ISSN: 1745-6215
CID: 4959342