tbuckley/cabot-search huggingface dataset:
Abstract 16950: Exosomes Derived From Podoplanin Positive Cells Induce Fibrosis and Inflammation in Healthy Mouse Heart
Authors: Maria Cimini, venkata naga srikanth garikipati, Andrea Elia, Chunlin Wang, MAY TRUONGCAO, Grace Huang, Vandana Mallaredy, Cindy Benedict, Raj Kishore
Journal: Circulation (2020)

Superseding fibrosis through paracrine signals enhances the ventricular dysfunction aftermyocardial infarction (MI). We have earlier reported that within 2 days post-MI a cohort ofpodoplanin (PDPN), a platelet aggregation-inducing type I transmembrane glycoprotein,positive cells populate injured heart and enhance inflammatory response by physicalinteractions with monocytes. Here we explored whether exosomes from these cells couldindependently alter healthy heart physiology and structure. PDPN+ cells were isolated 2 daysafter MI, cultured expanded and activated with TNFα and AngiotensinII. Exosomes derived fromactivated PDPN+ cells conditioned media were used in vitro treatment of mouse cardiacendothelial cells (mCECs), mouse embryonic fibroblast (MEF) and monocytes and in vivo forthe treatment of healthy mouse hearts. PDPN+ cells derived exosomes (PDPN-exo)reprogramed mCECs to the lymphatic phenotype enhancing the expression of the majorlymphatic lineage markers and upregulated the expression of fibrotic markers suggesting anendothelial-mesenchymal transition. Furthermore, PDPN-exo drove the MEF to myo-fibroblastphenotype and monocytes toward pro-inflammatory phenotype. Proteomic analysis of PDPN-exo suggest these transitions may depend on NOTCH cleavage trough β-γSecretase. In vivo,PDPN-exo were initially injected into the left ventricle of healthy mouse hearts followed withexosomes boosters delivered by retro-orbital vein injection. Treated mice developed anextended epicardial fibrosis with a subsequent impairment in the contractility and increase ofthe end diastolic and systolic volumes. The fibrotic area was characterized by vessels doublepositive to endothelial and lymphatic endothelial markers, and infiltrating CD45+ cells. Inconclusion these data suggest that PDPN-exo alter the biology of mCECs, fibroblast andmonocytes and participate in adverse remodeling after MI; their specific cargo may representa cohort of targets for the treatment of cardiac fibrosis.
Changes in Use of Left Ventricular Assist Devices as Bridge to Transplantation With New Heart Allocation Policy
Authors: Clancy W Mullan, Fouad Chouairi, Sounok Sen, Makoto Mori, Katherine A A Clark, Samuel W Reinhardt, P Elliott Miller, Michael A Fuery, Daniel Jacoby, Christopher Maulion, Muhammad Anwer, Arnar Geirsson, David Mulligan, Richard Formica, Joseph G Rogers, Nihar R Desai, Tariq Ahmad
Journal: JACC Heart Failure (2021)
A Transcriptomic Signature for Risk‐Stratification and Recurrence Prediction in Intrahepatic Cholangiocarcinoma
Authors: Yuma Wada, Mitsuo Shimada, Kensuke Yamamura, Takeo Toshima, Jasjit K Banwait, Yuji Morine, Tetsuya Ikemoto, Yu Saito, Hideo Baba, Masaki Mori, Ajay Goel
Journal: Hepatology (2021)

Background and Aims Tumor recurrence is frequent even in intrahepatic cholangiocarcinoma (ICC), and improved strategies are needed to identify patients at highest risk for such recurrence. We performed genome‐wide expression profile analyses to discover and validate a gene signature associated with recurrence in patients with ICC. Approach and Results For biomarker discovery, we analyzed genome‐wide transcriptomic profiling in ICC tumors from two public data sets: The Cancer Genome Atlas (n = 27) and GSE107943 (n = 28). We identified an eight‐gene panel ( BIRC5 [baculoviral IAP repeat containing 5], CDC20 [cell division cycle 20], CDH2 [cadherin 2], CENPW [centromere protein W], JPH1 [junctophilin 1], MAD2L1 [mitotic arrest deficient 2 like 1], NEIL3 [Nei like DNA glycosylase 3], and POC1A [POC1 centriolar protein A]) that robustly identified patients with recurrence in the discovery (AUC = 0.92) and in silico validation cohorts (AUC = 0.91). We next analyzed 241 specimens from patients with ICC (training cohort, n = 64; validation cohort, n = 177), followed by Cox proportional hazard regression analysis, to develop an integrated transcriptomic panel and establish a risk‐stratification model for recurrence in ICC. We subsequently trained this transcriptomic panel in a clinical cohort (AUC = 0.89; 95% confidence interval [CI] = 0.79‐0.95), followed by evaluating its performance in an independent validation cohort (AUC = 0.86; 95% CI = 0.80‐0.90). By combining our transcriptomic panel with various clinicopathologic features, we established a risk‐stratification model that was significantly superior for the identification of recurrence (AUC = 0.89; univariate HR = 6.08, 95% CI = 3.55‐10.41, P &lt; 0.01; and multivariate HR = 3.49, 95% CI = 1.81‐6.71, P &lt; 0.01). The risk‐stratification model identified potential recurrence in 85% of high‐risk patients and nonrecurrence in 76% of low‐risk patients, which is dramatically superior to currently used pathological features. Conclusions We report a transcriptomic signature for risk‐stratification and recurrence prediction that is superior to currently used clinicopathological features in patients with ICC.
P34.03 A ‘Plasma-First’ Molecular Profiling Approach Complements Actionable Mutation Detection in Suspected Lung Cancer Patients
Authors: J. Mong, J.L. Shi, A. Tee, K.C. Ngeow, J. Poh, Y. Choudhury, M. Tan
Journal: Journal of Thoracic Oncology (2021)
P84.22 Outcomes of TKI Treatment in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Real-World Study in Argentina
Authors: D. Kaen, F. Tsou, L. Lupinacci, C. Puparelli, J. Minatta, M. Rizzo, S. Berutti, R. Di Giovanni, Y. Ferreira, G. Recondo, O. Carranza, M. Flores, E. Aman, G. Di Mario, A. Pini, N. Castagneris, M. Roa, D. Enrico, C. Martin
Journal: Journal of Thoracic Oncology (2021)
Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy
Authors: Jichang Han, Yanding Zhao, Keisuke Shirai, Aleksey Molodtsov, Fred W. Kolling, Jan L. Fisher, Peisheng Zhang, Shaofeng Yan, Tyler G. Searles, Justin M. Bader, Jiang Gui, Chao Cheng, Marc S. Ernstoff, Mary Jo Turk, Christina V. Angeles
Journal: Nature Cancer (2021)
Exposure to indoor and airborne food allergens in commercial airplanes
Authors: Inês Paciência, João Cavaleiro Rufo, Mariana Farraia, Mariana Leal, André Moreira
Journal: Allergy (2021)

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How COVID-19 Affects the Brain
Authors: Maura Boldrini, Peter D. Canoll, Robyn S. Klein
Journal: JAMA Psychiatry (2021)

COVID-19 has resulted in more than 120 million cases and 2.6 million deaths to date.Respiratory and gastrointestinal symptoms are accompanied by short-and long-term neuropsychiatric symptoms (NPs) and long-term brain sequelae.Some patients present with anosmia, cognitive and attention deficits (ie, brain fog), new-onset anxiety, depression, psychosis, seizures, and even suicidal behavior. 1,2These present before, during, and after respiratory symptoms and are unrelated to respiratory insufficiency, 1 suggesting independent brain damage.Follow-ups conducted in Germany and the United Kingdom found post-COVID-19 NPs in 20% to 70% of patients, even in young adults, and lasting months after respiratory symptoms resolved, 1 suggesting brain involvement persists.Entering through angiotensin-converting enzyme 2 receptors, 2 SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi, and brain damage.Moreover, systemic inflammation leads to decreased monoamines and trophic factors and activation of microglia, resulting in increased glutamate and N-methyl-D-aspartate (NMDA) 3 and excitotoxicity (Figure).These insults induce newonset or re-exacerbation of preexisting NPs.
Compensatory combination of mTOR and TrxR inhibitors to cause oxidative stress and regression of tumors
Authors: Yiqun Xia, Jundixia Chen, Yun Yu, Fengjiao Wu, Xin Shen, Chenyu Qiu, Tingting Zhang, Lin Hong, Peisen Zheng, Rongrong Shao, Chenxin Xu, Fang Wu, Wei Chen, Congying Xie, Ri Cui, Peng Zou
Journal: Theranostics (2021)

Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
P76.55 Real-world Experience of the Utility in Afatinib Therapy for Patients with EGFR-Mutant Advanced NSCLC
Authors: S. Igawa, T. Ono, M. Kasajima, K. Yamada, A. Oguri, A. Kameda, H. Yamamoto, M. Kakegawa, Y. Hiyoshi, S. Kusuhara, T. Ozawa, S. Otani, T. Fukui, H. Mitsufuji, K. Masaru, M. Yokoba, M. Kubota, J. Sasaki, K. Naoki
Journal: Journal of Thoracic Oncology (2021)
Abstract 16054: Angiotensin II-Induced Aortic Inflammation and Remodeling Are Mitigated by the Actin-Binding Protein Drebrin
Authors: Lisheng Zhang, Jiao-Hui Wu, Tai-Qin Huang, Igor Nepliouev, Leigh Brian, Zhushan Zhang, Nathan P Rudemiller, Steven D Crowley, Neil J Freedman, Jonathan A Stiber
Journal: Circulation (2017)

The actin-binding protein Drebrin constrains smooth muscle cell (SMC) migration and proliferation in vitro and in vivo, and thereby reduces neointimal hyperplasia in response to arterial injury. We...
Inhibition of Caspase-1 with Tetracycline Ameliorates Acute Lung Injury
Authors: Konrad Peukert, Mario Fox, Susanne Schulz, Caroline Feuerborn, Stilla Frede, Christian Putensen, Hermann Wrigge, Beate Mareike Kümmerer, Sascha David, Benjamin Seeliger, Tobias Welte, Eicke Latz, Dennis Klinman, Christoph Wilhelm, Folkert Steinhagen, Christian Bode
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome with a mortality of up to 40%. Precision medicine approaches targeting patients on the basis of their molecular phenotypes of ARDS might help to identify effective pharmacotherapies. The inflammasome-caspase-1 pathway contributes to the development of ARDS via IL-1β and IL-18 production. Recent studies indicate that tetracycline can be used to treat inflammatory diseases mediated by IL-1β and IL-18, although the molecular mechanism by which tetracycline inhibits inflammasome-caspase-1 signaling remains unknown. Objectives: To identify patients with ARDS characterized by IL-1β and IL-18 expression and investigate the ability of tetracycline to inhibit inflammasome-caspase-1 signaling in ARDS. Methods: IL-1β and IL-18 concentrations were quantified in BAL fluid from patients with ARDS. Tetracycline's effects on lung injury and inflammation were assessed in two mouse models of direct (pulmonary) acute lung injury, and its effects on IL-1β and IL-18 production were assessed by alveolar leukocytes from patients with direct ARDS ex vivo. Murine macrophages were used to further characterize the effect of tetracycline on the inflammasome-caspase-1 pathway. Measurements and Main Results: BAL fluid concentrations of IL-1β and IL-18 are significantly higher in patients with direct ARDS than those with indirect (nonpulmonary) ARDS. In experimental acute lung injury, tetracycline significantly diminished lung injury and pulmonary inflammation by selectively inhibiting caspase-1-dependent IL-1β and IL-18 production, leading to improved survival. Tetracycline also reduced the production of IL-1β and IL-18 by alveolar leukocytes from patients with direct ARDS. Conclusions: Tetracycline may be effective in the treatment of direct ARDS in patients with elevated caspase-1 activity. Clinical Trial registered with www.clinicaltrials.gov (NCT04079426).
Racial/Ethnic Disparities in Very Preterm Birth and Preterm Birth Before and During the COVID-19 Pandemic
Authors: Teresa Janevic, Kimberly B. Glazer, Luciana Vieira, Ellerie Weber, Joanne Stone, Toni Stern, Angela Bianco, Brian Wagner, Siobhan M. Dolan, Elizabeth A. Howell
Journal: JAMA Network Open (2021)

The coronavirus disease 2019 (COVID-19) pandemic may exacerbate existing racial/ethnic inequities in preterm birth.To assess whether racial/ethnic disparities in very preterm birth (VPTB) and preterm birth (PTB) increased during the first wave of the COVID-19 pandemic in New York City.This cross-sectional study included 8026 Black, Latina, and White women who gave birth during the study period. A difference-in-differences (DID) analysis of Black vs White disparities in VPTB or PTB in a pandemic cohort was compared with a prepandemic cohort by using electronic medical records obtained from 2 hospitals in New York City.Women who delivered from March 28 to July 31, 2020, were considered the pandemic cohort, and women who delivered from March 28 to July 31, 2019, were considered the prepandemic cohort. Reverse transcription-polymerase chain reaction tests for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were performed using samples obtained via nasopharyngeal swab at the time of admission.Clinical estimates of gestational age were used to calculate VPTB (<32 weeks) and PTB (<37 weeks). Log binomial regression was performed to estimate Black vs White risk differences, pandemic cohort vs prepandemic cohort risk difference, and an interaction term representing the DID estimator. Covariate-adjusted models included age, insurance, prepregnancy body mass index, and parity.Of 3834 women in the pandemic cohort, 492 (12.8%) self-identified as Black, 678 (17.7%) as Latina, 2012 (52.5%) as White, 408 (10.6%) as Asian, and 244 (6.4%) as other or unspecified race/ethnicity, with approximately half the women 25 to 34 years of age. The prepandemic cohort comprised 4192 women with similar sociodemographic characteristics. In the prepandemic cohort, VPTB risk was 4.4% (20 of 451) and PTB risk was 14.4% (65 of 451) among Black infants compared with 0.8% (17 of 2188) VPTB risk and 7.1% (156 of 2188) PTB risk among White infants. In the pandemic cohort, VPTB risk was 4.3% (21 of 491) and PTB risk was 13.2% (65 of 491) among Black infants compared with 0.5% (10 of 1994) VPTB risk and 7.0% (240 of 1994) PTB risk among White infants. The DID estimators indicated that no increase in Black vs White disparities were found (DID estimator for VPTB, 0.1 additional cases per 100 [95% CI, -2.5 to 2.8]; DID estimator for PTB, 1.1 fewer case per 100 [95% CI, -5.8 to 3.6]). The results were comparable in covariate-adjusted models when limiting the population to women who tested negative for SARS-CoV-2. No change was detected in Latina vs White PTB disparities during the pandemic.In this cross-sectional study of women who gave birth in New York City during the COVID-19 pandemic, no evidence was found for increased racial/ethnic disparities in PTB, among women who tested positive or tested negative for SARS-CoV-2.
The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action
Authors: Rong Chen, Jennifer Tsai, Philip A. Thompson, Yuling Chen, Ping Xiong, Chaomei Liu, Francis Burrows, Mariela Sivina, Jan A. Burger, Michael J. Keating, William G. Wierda, William Plunkett
Journal: Blood Cancer Journal (2021)

The constitutive activation of B-cell receptor (BCR) signaling, together with the overexpression of the Bcl-2 family anti-apoptotic proteins, represents two hallmarks of chronic lymphocytic leukemia (CLL) that drive leukemia cell proliferation and sustain their survival. TG02 is a small molecule multi-kinase inhibitor that simultaneously targets both of these facets of CLL pathogenesis. First, its inhibition of cyclin-dependent kinase 9 blocked the activation of RNA polymerase II and transcription. This led to the depletion of Mcl-1 and rapid induction of apoptosis in the primary CLL cells. This mechanism of apoptosis was independent of CLL prognostic factors or prior treatment history, but dependent on the expression of BAX and BAK. Second, TG02, which inhibits the members of the BCR signaling pathway such as Lck and Fyn, blocked BCR-crosslinking-induced activation of NF-κB and Akt, indicating abrogation of BCR signaling. Finally, the combination of TG02 and ibrutinib demonstrated moderate synergy, suggesting a future combination of TG02 with ibrutinib, or use in patients that are refractory to the BCR antagonists. Thus, the dual inhibitory activity on both the CLL survival pathway and BCR signaling identifies TG02 as a unique compound for clinical development in CLL and possibly other B cell malignancies.
The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells
Authors: Prashant V. Bommi, Charles M. Bowen, Laura Reyes-Uribe, Wenhui Wu, Hiroyuki Katayama, Pedro Rocha, Edwin R. Parra, Alejandro Francisco-Cruz, Zuhal Ozcan, Elena Tosti, Jason A. Willis, Hong Wu, Melissa W. Taggart, Jared K. Burks, Patrick M. Lynch, Winfried Edelmann, Paul A. Scheet, Ignacio I. Wistuba, Krishna M. Sinha, Samir M. Hanash, Eduardo Vilar
Journal: Cancer Research (2021)

Abstract Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2LoxP/LoxP) was crossed with a reporter mouse (Lgr5-EGFP-IRES-creERT2) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (Msh2-KO, Msh2-HET, and Msh2-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR, IHC, and whole transcriptomic sequencing in mouse tissues, organoids, and a cohort of human samples, including normal colorectal mucosa, premalignant lesions, and early-stage colorectal cancers from patients with Lynch syndrome and patients with familial adenomatous polyposis (FAP) as controls. Msh2-KO ISCs clustered together with differentiated intestinal epithelial cells from all genotypes. Gene-set enrichment analysis indicated inhibition of replication, cell-cycle progression, and the Wnt pathway and activation of epithelial signaling and immune reaction. An expression signature derived from MMRd ISCs successfully distinguished MMRd neoplastic lesions of patients with Lynch syndrome from FAP controls. SPP1 was specifically upregulated in MMRd ISCs and colocalized with LGR5 in Lynch syndrome colorectal premalignant lesions and tumors. These results show that expression signatures of MMRd ISC recapitulate the initial steps of Lynch syndrome carcinogenesis and have the potential to unveil novel biomarkers of early cancer initiation. Significance: The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression.
Survival in Immunocompromised Patients Ultimately Requiring Invasive Mechanical Ventilation: A Pooled Individual Patient Data Analysis
Authors: Guillaume Dumas, Virginie Lemiale, Nisha Rathi, Andrea Cortegiani, Frédéric Pène, Vincent Bonny, Jorge Salluh, Guillermo M. Albaiceta, Marcio Soares, Ayman O. Soubani, Emmanuel Canet, Tarik Hanane, Achille Kouatchet, Djamel Mokart, Pia Lebiedz, Melda Türkoğlu, Rémi Coudroy, Kyeongman Jeon, Alexandre Demoule, Sangeeta Mehta, Pedro Caruso, Jean-Pierre Frat, Kuang-Yao Yang, Oriol Roca, John Laffey, Jean-François Timsit, Elie Azoulay, Michael Darmon
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Acute respiratory failure (ARF) is associated with high mortality in immunocompromised patients, particularly when invasive mechanical ventilation is needed. Therefore, noninvasive oxygenation/ventilation strategies have been developed to avoid intubation, with uncertain impact on mortality, especially when intubation is delayed. Objectives: We sought to report trends of survival over time in immunocompromised patients receiving invasive mechanical ventilation. The impact of delayed intubation after failure of noninvasive strategies was also assessed. Methods: Systematic review and meta-analysis using individual patient data of studies that focused on immunocompromised adult patients with ARF requiring invasive mechanical ventilation. Studies published in English were identified through PubMed, Web of Science, and Cochrane Central (2008-2018). Individual patient data were requested from corresponding authors for all identified studies. We used mixed-effect models to estimate the effect of delayed intubation on hospital mortality and described mortality rates over time. Measurements and Main Results: A total of 11,087 patients were included (24 studies, three controlled trials, and 21 cohorts), of whom 7,736 (74%) were intubated within 24 hours of ICU admission (early intubation). The crude mortality rate was 53.2%. Adjusted survivals improved over time (from 1995 to 2017, odds ratio [OR] for hospital mortality per year, 0.96 [0.95-0.97]). For each elapsed day between ICU admission and intubation, mortality was higher (OR, 1.38 [1.26-1.52]; P < 0.001). Early intubation was significantly associated with lower mortality (OR, 0.83 [0.72-0.96]), regardless of initial oxygenation strategy. These results persisted after propensity score analysis (matched OR associated with delayed intubation, 1.56 [1.44-1.70]). Conclusions: In immunocompromised intubated patients, survival has improved over time. Time between ICU admission and intubation is a strong predictor of mortality, suggesting a detrimental effect of late initial oxygenation failure.
Valve Strain Quantitation in Normal Mitral Valves and Mitral Prolapse With Variable Degrees of Regurgitation
Authors: K. Carlos El-Tallawi, Peng Zhang, Robert Azencott, Jiwen He, Elizabeth L. Herrera, Jiaqiong Xu, Mohammed Chamsi-Pasha, Jessen Jacob, Gerald M. Lawrie, William A. Zoghbi
Journal: JACC. Cardiovascular imaging (2021)
Automated evaluation of tumor spheroid behavior in 3D culture using deep learning-based recognition
Authors: Zaozao Chen, Ning Ma, Xiaowei Sun, Qiwei Li, Yi Zeng, Fei Chen, Shiqi Sun, Jun Xu, Jing Zhang, Huan Ye, Jianjun Ge, Zheng Zhang, Xingran Cui, Kam Leong, Yang Chen, Zhongze Gu
Journal: Biomaterials (2021)